Ezetimibe and Simvastatin (Page 8 of 11)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

E zetimibe and simvastatin

No animal carcinogenicity or fertility studies have been conducted with the combination of ezetimibe and simvastatin. The combination of ezetimibe with simvastatin did not show evidence of mutagenicity 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 ezetimibe and simvastatin with or without metabolic activation. There was no evidence of genotoxicity at doses up to 600 mg/kg with the combination of ezetimibe and simvastatin (1:1) in the in vivo mouse micronucleus test.

Ezetimibe

A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1,500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times 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 times 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 1,000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe).

Simvastatin

In a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of 25, 100, and 400 mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8 times higher than the mean human plasma drug level, respectively, (as total inhibitory activity based on AUC) after an 80-mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males with a maximum incidence of 90% in males. The incidence of adenomas of the liver was significantly increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No evidence of a tumorigenic effect was observed at 25 mg/kg/day.

In a separate 92-week carcinogenicity study in mice at doses up to 25 mg/kg/day, no evidence of a tumorigenic effect was observed (mean plasma drug levels were 1 times higher than humans given 80 mg simvastatin as measured by AUC).

In a two-year study in rats at 25 mg/kg/day, there was a statistically significant increase in the incidence of thyroid follicular adenomas in female rats exposed to approximately 11 times higher levels of simvastatin than in humans given 80 mg simvastatin (as measured by AUC).

A second two-year rat carcinogenicity study with doses of 50 and 100 mg/kg/day produced hepatocellular adenomas and carcinomas (in female rats at both doses and in males at 100 mg/kg/day). Thyroid follicular cell adenomas were increased in males and females at both doses; thyroid follicular cell carcinomas were increased in females at 100 mg/kg/day. The increased incidence of thyroid neoplasms appears to be consistent with findings from other statins. These treatment levels represented plasma drug levels (AUC) of approximately 7 and 15 times (males) and 22 and 25 times (females) the mean human plasma drug exposure after an 80-mg daily dose.

No evidence of mutagenicity was observed in a microbial mutagenicity (Ames) test with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow.

There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg body weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/day); however, this effect was not observed during a subsequent fertility study in which simvastatin was administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation). No microscopic changes were observed in the testes of rats from either study. At 180 mg/kg/day (which produces exposure levels 22 times higher than those in humans taking 80 mg/day based on surface area, mg/m2), seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day (approximately 2 times the human exposure, based on AUC, at 80 mg/day). The clinical significance of these findings is unclear.

13.2 Animal Toxicology and/or Pharmacology

CNS Toxicity

Optic nerve degeneration was seen in clinically normal dogs treated with simvastatin for 14 weeks at 180 mg/kg/day, a dose that produced mean plasma drug levels about 12 times higher than the mean plasma drug level in humans taking 80 mg/day.

A chemically similar drug in this class also produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean plasma drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose that resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose.

CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels, were seen in dogs treated with simvastatin at a dose of 360 mg/kg/day, a dose that produced mean plasma drug levels that were about 14 times higher than the mean plasma drug levels in humans taking 80 mg/day. Similar CNS vascular lesions have been observed with several other drugs of this class.

There were cataracts in female rats after two years of treatment with 50 and 100 mg/kg/day (22 and 25 times the human AUC at 80 mg/day, respectively) and in dogs after three months at 90 mg/kg/day (19 times) and at two years at 50 mg/kg/day (5 times).

Ezetimibe

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 being a potent cholesterol absorption inhibitor.

In a rat model, where the glucuronide metabolite of ezetimibe (ezetimibe-glucuronide) was administered intraduodenally, the metabolite was as potent as ezetimibe 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 mg/kg/day 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 mg/kg/day 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 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

E zetimibe and simvastatin

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

Ezetimibe and simvastatin is effective in men and women with hyperlipidemia. Experience in non-Caucasians is limited and does not permit a precise estimate of the magnitude of the effects of ezetimibe and simvastatin.

Five multicenter, double-blind studies conducted with either ezetimibe and simvastatin or co-administered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin in patients with primary hyperlipidemia are reported: two were comparisons with simvastatin, two were comparisons with atorvastatin, and one was a comparison with rosuvastatin.

In a multicenter, double-blind, placebo-controlled, 12-week trial, 1,528 hyperlipidemic patients were randomized to one of ten treatment groups: placebo, ezetimibe (10 mg), simvastatin (10 mg, 20 mg, 40 mg, or 80 mg), or ezetimibe and simvastatin (10/10, 10/20, 10/40, or 10/80).

When patients receiving ezetimibe and simvastatin were compared to those receiving all doses of simvastatin, ezetimibe and simvastatin significantly lowered total-C, LDL-C, Apo B, TG, and non-HDL-C. The effects of ezetimibe and simvastatin on HDL-C were similar to the effects seen with simvastatin. Further analysis showed ezetimibe and simvastatin significantly increased HDL-C compared with placebo (see Table 7). The lipid response to ezetimibe and simvastatin was similar in patients with TG levels greater than or less than 200 mg/dL.

Table 7: Response to Ezetimibe and simvastatin in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline)

Treatment

(Daily Dose)

N

Total-C

LDL-C

Apo B

HDL-C

TG*

Non-HDL-

C

Pooled data (All ezetimibe and simvastatin doses)

609

-38

-53

-42

+7

-24

-49

Pooled data (All simvastatin

doses)

622

-28

-39

-32

+7

-21

-36

Ezetimibe 10 mg

149

-13

-19

-15

+5

-11

-18

Placebo

148

-1

-2

0

0

-2

-2

Ezetimibe and simvastatin by dose

10/10

152

-31

-45

-35

+8

-23

-41

10/20

156

-36

-52

-41

+10

-24

-47

10/40

147

-39

-55

-44

+6

-23

-51

10/80

154

-43

-60

-49

+6

-31

-56

Simvastatin by dose

10 mg

158

-23

-33

-26

+5

-17

-30

20 mg

150

-24

-34

-28

+7

-18

-32

40 mg

156

-29

-41

-33

+8

-21

-38

80 mg

158

-35

-49

-39

+7

-27

-45

* For triglycerides, median % change from baseline.

Baseline — on no lipid-lowering drug.

Ezetimibe and simvastatin doses pooled (10/10 to 10/80) significantly reduced total-C, LDL-C, Apo B, TG, and non-HDL-C compared to simvastatin and significantly increased HDL-C compared to placebo.

In a multicenter, double-blind, controlled, 23-week study, 710 patients with known CHD or CHD risk equivalents, as defined by the NCEP ATP III guidelines, and an LDL-C ≥130 mg/dL were randomized to one of four treatment groups: co-administered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin (10/10, 10/20, and 10/40) or simvastatin 20 mg. Patients not reaching an LDL-C <100 mg/dL had their simvastatin dose titrated at 6-week intervals to a maximal dose of 80 mg.

At Week 5, the LDL-C reductions with ezetimibe and simvastatin 10/10, 10/20, or 10/40 were significantly larger than with simvastatin 20 mg (see Table 8).

Table 8: Response to E zetimibe and simvastatin after 5 Weeks in Patients with CHD or CHD Risk Equivalents and an LDL-C ≥130 mg/dL

Simvastatin

20 mg

E zetimibe and simvastatin10/10

E zetimibe and simvastatin 10/20

E zetimibe and simvastatin 10/40

N

253

251

109

97

Mean baseline LDL-C

174

165

167

171

Percent change LDL-C

-38

-47

-53

-59

In a multicenter, double-blind, 6-week study, 1,902 patients with primary hyperlipidemia, who had not met their NCEP ATP III target LDL-C goal, were randomized to one of eight treatment groups: ezetimibe and simvastatin (10/10, 10/20, 10/40, or 10/80) or atorvastatin (10 mg, 20 mg, 40 mg, or 80 mg).

Across the dosage range, when patients receiving ezetimibe and simvastatin were compared to those receiving milligram-equivalent statin doses of atorvastatin, ezetimibe and simvastatin lowered total-C, LDL-C, Apo B, and non-HDL-C significantly more than atorvastatin. Only the 10/40 mg and 10/80 mg ezetimibe and simvastatin doses increased HDL-C significantly more than the corresponding milligram-equivalent statin dose of atorvastatin. The effects of ezetimibe and simvastatin on TG were similar to the effects seen with atorvastatin (see Table 9).

Table 9: Response to Ezetimibe and simvastatin and Atorvastatin in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline)

Treatment

(Daily Dose)

N

Total-C

LDL-C

Apo B

HDL-C

TG*

Non-HDL-

C

Ezetimibe and simvastatin by dose

10/10

230

-34§

-47§

-37§

+8

-26

-43§

10/20

233

-37§

-51§

-40§

+7

-25

-46§

10/40

236

-41§

-57§

-46§

+9§

-27

-52§

10/80

224

-43§

-59§

-48§

+8§

-31

-54§

Atorvastatin by dose

10 mg

235

-27

-36

-31

+7

-21

-34

20 mg

230

-32

-44

-37

+5

-25

-41

40 mg

232

-36

-48

-40

+4

-24

-45

80 mg

230

-40

-53

-44

+1

-32

-50

* For triglycerides, median % change from baseline.

Baseline — on no lipid-lowering drug.

Ezetimibe and simvastatin doses pooled (10/10 to 10/80) provided significantly greater reductions in total-C, LDL-C, Apo B, and non-HDL-C compared to atorvastatin doses pooled (10 to 80).

§ p<0.05 for difference with atorvastatin at equal mg doses of the simvastatin component.

In a multicenter, double-blind, 24-week, forced-titration study, 788 patients with primary hyperlipidemia, who had not met their NCEP ATP III target LDL-C goal, were randomized to receive co-administered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin (10/10 and 10/20) or atorvastatin 10 mg. For all three treatment groups, the dose of the statin was titrated at 6-week intervals to 80 mg. At each pre-specified dose comparison, ezetimibe and simvastatin lowered LDL-C to a greater degree than atorvastatin (see Table 10).

Table 10: Response to E zetimibe and simvastatin and Atorvastatin in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline)

Treatment

N

Total-C

LDL-C

Apo B

HDL-C

TG*

Non-HDL-

C

Week 6

Atorvastatin 10 mg

262

-28

-37

-32

+5

-23

-35

Ezetimibe and simvastatin 10/10§

263

-34

-46

-38

+8

-26

-43

Ezetimibe and simvastatin 10/20#

263

-36

-50

-41

+10

-25

-46

Week 12

Atorvastatin 20 mg

246

-33

-44

-38

+7

-28

-42

Ezetimibe and simvastatin 10/20

250

-37

-50

-41

+9

-28

-46

Ezetimibe and simvastatin 10/40

252

-39

-54

-45

+12

-31

-50

Week 18

Atorvastatin 40 mg

237

-37

-49

-42

+8

-31

-47

Ezetimibe and simvastatin 10/40Þ

482

-40

-56

-45

+11

-32

-52

Week 24

Atorvastatin 80 mg

228

-40

-53

-45

+6

-35

-50

Ezetimibe and simvastatin 10/80Þ

459

-43

-59

-49

+12

-35

-55

* For triglycerides, median % change from baseline.

Baseline — on no lipid-lowering drug.

Atorvastatin: 10 mg start dose titrated to 20 mg, 40 mg, and 80 mg through Weeks 6, 12, 18, and 24.

§ Ezetimibe and simvastatin: 10/10 start dose titrated to 10/20, 10/40, and 10/80 through Weeks 6, 12, 18, and 24.

p≤0.05 for difference with atorvastatin in the specified week.

# Ezetimibe and simvastatin: 10/20 start dose titrated to 10/40, 10/40, and 10/80 through Weeks 6, 12, 18, and 24.

Þ Data pooled for common doses of ezetimibe and simvastatin at Weeks 18 and 24.

In a multicenter, double-blind, 6-week study, 2,959 patients with primary hyperlipidemia, who had not met their NCEP ATP III target LDL-C goal, were randomized to one of six treatment groups: ezetimibe and simvastatin (10/20, 10/40, or 10/80) or rosuvastatin (10 mg, 20 mg, or 40 mg).

The effects of ezetimibe and simvastatin and rosuvastatin on total-C, LDL-C, Apo B, TG, non-HDL-C and HDL-C are shown in Table 11.

Table 11: Response to E zetimibe and simvastatin and Rosuvastatin in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline)

Treatment

(Daily Dose)

N

Total-C

LDL-C

Apo B

HDL-C

TG*

Non-HDL-

C

Ezetimibe and simvastatin by dose

10/20

476

-37§

-52§

-42§

+7

-23§

-47§

10/40

477

-39

-55

-44

+8

-27

-50

10/80

474

-44#

-61#

-50#

+8

-30#

-56#

Rosuvastatin by dose

10 mg

475

-32

-46

-37

+7

-20

-42

20 mg

478

-37

-52

-43

+8

-26

-48

40 mg

475

-41

-57

-47

+8

-28

-52

* For triglycerides, median % change from baseline.

Baseline — on no lipid-lowering drug.

Ezetimibe and simvastatin doses pooled (10/20 to 10/80) provided significantly greater reductions in total-C, LDL-C, Apo B, and non-HDL-C compared to rosuvastatin doses pooled (10 mg to 40 mg).

§ p<0.05 vs. rosuvastatin 10 mg.

p<0.05 vs. rosuvastatin 20 mg.

# p<0.05 vs. rosuvastatin 40 mg.

In a multicenter, double-blind, 24-week trial, 214 patients with type 2 diabetes mellitus treated with thiazolidinediones (rosiglitazone or pioglitazone) for a minimum of 3 months and simvastatin 20 mg for a minimum of 6 weeks were randomized to receive either simvastatin 40 mg or the co-administered active ingredients equivalent to ezetimibe and simvastatin 10/20. The median LDL-C and HbA1c levels at baseline were 89 mg/dL and 7.1%, respectively.

Ezetimibe and simvastatin 10/20 was significantly more effective than doubling the dose of simvastatin to 40 mg. The median percent changes from baseline for ezetimibe and simvastatin vs. simvastatin were: LDL-C -25% and -5%; total-C -16% and -5%; Apo B -19% and -5%; and non-HDL-C -23% and -5%. Results for HDL-C and TG between the two treatment groups were not significantly different.

Ezetimibe

In two multicenter, double-blind, placebo-controlled, 12-week studies in 1,719 patients with primary hyperlipidemia, ezetimibe significantly lowered total-C (-13%), LDL-C (-19%), Apo B (-14%), and TG (-8%), and increased HDL-C (+3%) compared to placebo. Reduction in LDL-C was consistent across age, sex, and baseline LDL-C.

Simvastatin

In two large, placebo-controlled clinical trials, the Scandinavian Simvastatin Survival Study (N=4,444 patients) and the Heart Protection Study (N=20,536 patients), the effects of treatment with simvastatin were assessed in patients at high risk of coronary events because of existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease. Simvastatin was proven to reduce: the risk of total mortality by reducing CHD deaths; the risk of non-fatal myocardial infarction and stroke; and the need for coronary and non-coronary revascularization procedures.

No incremental benefit of ezetimibe and simvastatin on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.

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