Ezetimibe and Simvastatin (ezetimibe 10 mg simvastatin 80 mg) Dailymed

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Ezetimibe and Simvastatin Tablets

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 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~ 20 times the human exposure at 10 mg daily based on AUC _0-24hr 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 AUC _0-24hr 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 times the human exposure at 10 mg daily based on AUC _0-24hr 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/m ²), 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 ED ₅₀ value of 0.5 mcg/kg/day for inhibiting the rise in plasma cholesterol levels in monkeys. The ED ₅₀ 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 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 for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of ¹⁴C-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 and Simvastatin Tablets

Ezetimibe and simvastatin tablets reduce 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 tablets are 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 tablets.

Five multicenter, double-blind studies conducted with either ezetimibe and simvastatin tablets or coadministered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin tablets 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 tablets (10 mg/10 mg, 10 mg/20 mg, 10 mg/40 mg, or 10 mg/80 mg).

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

Table 7: Response to Ezetimibe and Simvastatin Tablets in Patients with Primary Hyperlipidemia (Mean For triglycerides, median % change from baseline. % Change from Untreated Baseline2)

Treatment (Daily Dose)	N	Total-C	LDL-C	Apo B	HDL-C	TG	Non-HDL-C
Pooled data (All ezetimibe and simvastatin tablet doses) Ezetimibe and simvastatin tablet doses pooled (10 mg/10 mg to 10 mg/80 mg) significantly reduced total-C, LDL-C, Apo B, TG, and non-HDL-C compared to simvastatin and significantly increased HDL-C compared to placebo.	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 tablets by dose
10 mg/10 mg	152	-31	-45	-35	+8	-23	-41
10 mg/20 mg	156	-36	-52	-41	+10	-24	-47
10 mg/40 mg	147	-39	-55	-44	+6	-23	-51
10 mg/80 mg	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

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: coadministered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin tablets (10 mg/10 mg, 10 mg/20 mg, and 10 mg/40 mg) 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 tablets 10 mg/10 mg, 10 mg/20 mg, or 10 mg/40 mg were significantly larger than with simvastatin 20 mg (see Table 8).

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

	Simvastatin	Ezetimibe and Simvastatin Tablets,	Ezetimibe and Simvastatin Tablets,	Ezetimibe and Simvastatin Tablets,
	20 mg	10 mg/10 mg	10 mg/20 mg	10 mg/40 mg
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 tablets (10 mg/10 mg, 10 mg/20 mg, 10 mg/40 mg, or 10 mg/80 mg) or atorvastatin (10 mg, 20 mg, 40 mg, or 80 mg).

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

Table 9: Response to Ezetimibe and Simvastatin Tablets and Atorvastatin in Patients with Primary Hyperlipidemia (Mean For triglycerides, median % change from baseline. % Change from Untreated Baseline Baseline - on no lipid-lowering drug.)

Treatment (Daily Dose)	N	Total-C Ezetimibe and simvastatin tablet doses pooled (10 mg/10 mg to 10 mg/80 mg) provided significantly greater reductions in total-C, LDL-C, Apo B, and non-HDL-C compared to atorvastatin doses pooled (10 mg to 80 mg).	LDL-C	Apo B	HDL-C	TG	Non-HDL-C
Ezetimibe and simvastatin tablets by dose
10 mg/10 mg	230	-34 p < 0.05 for difference with atorvastatin at equal mg doses of the simvastatin component.	-47	-37	+8	-26	-43
10 mg/20 mg	233	-37	-51	-40	+7	-25	-46
10 mg/40 mg	236	-41	-57	-46	+9	-27	-52
10 mg/80 mg	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

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 coadministered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin tablets (10 mg/10 mg and 10 mg/20 mg) 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 tablets lowered LDL-C to a greater degree than atorvastatin (see Table 10).

Table 10: Response to Ezetimibe and Simvastatin Tablets and Atorvastatin in Patients with Primary Hyperlipidemia (Mean For triglycerides, median % change from baseline. % Change from Untreated Baseline Baseline - on no lipid-lowering drug.)

Treatment	N	Total-C	LDL-C	Apo B	HDL-C	TG	Non-HDL-C
Week 6
Atorvastatin 10 mg Atorvastatin: 10 mg start dose titrated to 20 mg, 40 mg, and 80 mg through Weeks 6, 12, 18, and 24.	262	-28	-37	-32	+5	-23	-35
Ezetimibe and simvastatin tablets, 10 mg/10 mg Ezetimibe and simvastatin tablets: 10 mg/10 mg start dose titrated to 10 mg/20 mg, 10 mg/40 mg, and 10 mg/80 mg through Weeks 6, 12, 18, and 24.	263	-34 p ≤ 0.05 for difference with atorvastatin in the specified week.	-46	-38	+8	-26	-43
Ezetimibe and simvastatin tablets, 10 mg/20 mg Ezetimibe and simvastatin tablets: 10 mg/20 mg start dose titrated to 10 mg/40 mg, 10 mg/40 mg, and 10 mg/80 mg through Weeks 6, 12, 18, and 24.	263	-36	-50	-41	+10	-25	-46
Week 12
Atorvastatin 20 mg	246	-33	-44	-38	+7	-28	-42
Ezetimibe and simvastatin tablets, 10 mg/20 mg	250	-37	-50	-41	+9	-28	-46
Ezetimibe and simvastatin tablets, 10 mg/40 mg	252	-39	-54	-45	+12	-31	-50
Week 18
Atorvastatin 40 mg	237	-37	-49	-42	+8	-31	-47
Ezetimibe and simvastatin tablets, 10 mg/40 mg Data pooled for common doses of ezetimibe and simvastatin tablets at Weeks 18 and 24.	482	-40	-56	-45	+11	-32	-52
Week 24
Atorvastatin 80 mg	228	-40	-53	-45	+6	-35	-50
Ezetimibe and simvastatin tablets, 10 mg/80 mg	459	-43	-59	-49	+12	-35	-55

In a multicenter, double-blind, 6 week study, 2959 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 tablets (10 mg/20 mg, 10 mg/40 mg, or 10 mg/80 mg) or rosuvastatin (10 mg, 20 mg, or 40 mg).

The effects of ezetimibe and simvastatin tablets 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 Ezetimibe and Simvastatin Tablets and Rosuvastatin in Patients with Primary Hyperlipidemia (Mean For triglycerides, median % change from baseline. % Change from Untreated Baseline Baseline - on no lipid-lowering drug.)

Treatment (Daily Dose)	N	Total-C Ezetimibe and simvastatin tablet doses pooled (10 mg/20 mg to 10 mg/80 mg) 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).	LDL-C	Apo B	HDL-C	TG	Non-HDL-C
Ezetimibe and simvastatin tablets by dose
10 mg/20 mg	476	-37 p < 0.05 vs. rosuvastatin 10 mg.	-52	-42	+7	-23	-47
10 mg/40 mg	477	-39 p < 0.05 vs. rosuvastatin 20 mg.	-55	-44	+8	-27	-50
10 mg/80 mg	474	-44 p < 0.05 vs. rosuvastatin 40 mg.	-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

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 coadministered active ingredients equivalent to ezetimibe and simvastatin tablets, 10 mg/20 mg. The median LDL-C and HbA1c levels at baseline were 89 mg/dL and 7.1%, respectively.

Ezetimibe and simvastatin tablets, 10 mg/20 mg were significantly more effective than doubling the dose of simvastatin to 40 mg. The median percent changes from baseline for ezetimibe and simvastatin tablets 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 tablets on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.

14.2 Homozygous Familial Hypercholesterolemia (HoFH)

A double-blind, randomized, 12 week study was performed in patients with a clinical and/or genotypic diagnosis of HoFH. Data were analyzed from a subgroup of patients (n = 14) receiving simvastatin 40 mg at baseline. Increasing the dose of simvastatin from 40 mg to 80 mg (n = 5) produced a reduction of LDL-C of 13% from baseline on simvastatin 40 mg. Coadministered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin tablets (10 mg/40 mg and 10 mg/80 mg pooled, n = 9), produced a reduction of LDL-C of 23% from baseline on simvastatin 40 mg. In those patients coadministered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin tablets (10 mg/80 mg, n = 5), a reduction of LDL-C of 29% from baseline on simvastatin 40 mg was produced.

14.3 Chronic Kidney Disease (CKD)

The Study of Heart and Renal Protection (SHARP) was a multinational, randomized, placebo-controlled, double-blind trial that investigated the effect of ezetimibe and simvastatin on the time to a first major vascular event (MVE) among 9438 patients with moderate to severe chronic kidney disease (approximately one-third on dialysis at baseline) who did not have a history of myocardial infarction or coronary revascularization. An MVE was defined as nonfatal MI, cardiac death, stroke, or any revascularization procedure. Patients were allocated to treatment using a method that took into account the distribution of 8 important baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups.

For the first year, 9,438 patients were allocated 4:4:1, to ezetimibe and simvastatin tablets, 10 mg/20 mg, placebo, or simvastatin 20 mg daily, respectively. The 1 year simvastatin arm enabled the comparison of ezetimibe and simvastatin to simvastatin with regard to safety and effect on lipid levels. At 1 year the simvastatin-only arm was re-allocated 1:1 to ezetimibe and simvastatin tablets, 10 mg/20 mg or placebo. A total of 9,270 patients were ever allocated to ezetimibe and simvastatin tablets, 10 mg/20 mg (n = 4,650) or placebo (n = 4,620) during the trial. The median follow-up duration was 4.9 years. Patients had a mean age of 61 years; 63% were male, 72% were Caucasian, and 23% were diabetic; and, for those not on dialysis at baseline, the median serum creatinine was 2.5 mg/dL and the median estimated glomerular filtration rate (eGFR) was 25.6 mL/min/1.73 m ², with 94% of patients having an eGFR < 45 mL/min/1.73m ². Eligibility did not depend on lipid levels. Mean LDL-C at baseline was 108 mg/dL. At 1 year, the mean LDL-C was 26% lower in the simvastatin arm and 38% lower in the ezetimibe and simvastatin arm relative to placebo. At the midpoint of the study (2.5 years), the mean LDL-C was 32% lower for ezetimibe and simvastatin relative to placebo. Patients no longer taking study medication were included in all lipid measurements.

In the primary intent-to-treat analysis, 639 (15.2%) of 4,193 patients initially allocated to ezetimibe and simvastatin and 749 (17.9%) of 4,191 patients initially allocated to placebo experienced an MVE. This corresponded to a relative risk reduction of 16% (p = 0.001) (see Figure 1). Similarly, 526 (11.3%) of 4,650 patients ever allocated to ezetimibe and simvastatin and 619 (13.4%) of 4620 patients ever allocated to placebo experienced a major atherosclerotic event (MAE; a subset of the MVE composite that excluded non-coronary cardiac deaths and hemorrhagic stroke), corresponding to a relative risk reduction of 17% (p = 0.002). The trial demonstrated that treatment with ezetimibe and simvastatin tablets, 10 mg/20 mg versus placebo reduced the risk for MVE and MAE in this CKD population. The study design precluded drawing conclusions regarding the independent contribution of either ezetimibe or simvastatin to the observed effect.

The treatment effect of ezetimibe and simvastatin on MVE was attenuated among patients on dialysis at baseline compared with those not on dialysis at baseline. Among 3,023 patients on dialysis at baseline, ezetimibe and simvastatin reduced the risk of MVE by 6% (RR 0.94: 95% CI 0.80 to 1.09) compared with 22% (RR 0.78: 95% CI 0.69 to 0.89) among 6,247 patients not on dialysis at baseline (interaction P = 0.08).

The individual components of MVE in all patients ever allocated to ezetimibe and simvastatin or placebo are presented in Table 12.

Table 12: Number of First Events for Each Component of the Major Vascular Event Composite Endpoint in SHARP Intention-to-treat analysis on all SHARP patients ever allocated to ezetimibe and simvastatin or placebo.

Outcome	Ezetimibe and Simvastatin 10 mg/20 mg	Placebo	Risk Ratio	P-value
	(N = 4650)	(N = 4620)	(95% CI)
Major Vascular Events	701 (15.1%)	814 (17.6%)	0.85 (0.77 to 0.94)	0.001
Nonfatal MI	134 (2.9%)	159 (3.4%)	0.84 (0.66 to 1.05)	0.12
Cardiac Death	253 (5.4%)	272 (5.9%)	0.93 (0.78 to 1.10)	0.38
Any Stroke	171 (3.7%)	210 (4.5%)	0.81 (0.66 to 0.99)	0.038
Non-hemorrhagic Stroke	131 (2.8%)	174 (3.8%)	0.75 (0.60 to 0.94)	0.011
Hemorrhagic Stroke	45 (1.0%)	37 (0.8%)	1.21 (0.78 to 1.86)	0.40
Any Revascularization	284 (6.1%)	352 (7.6%)	0.79 (0.68 to 0.93)	0.004

Among patients not on dialysis at baseline, ezetimibe and simvastatin did not reduce the risk of progressing to end-stage renal disease compared with placebo (RR 0.97: 95% CI 0.89 to 1.05).

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel.

Patients should be advised about substances they should not take concomitantly with ezetimibe and simvastatin tablets [ see Contraindications ( 4) and Warnings and Precautions ( 5.1) ]. Patients should also be advised to inform other healthcare professionals prescribing a new medication or increasing the dose of an existing medication that they are taking ezetimibe and simvastatin tablets.

17.1 Muscle Pain

All patients starting therapy with ezetimibe and simvastatin tablets should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing ezetimibe and simvastatin tablets. Patients using the 10 mg/80 mg dose should be informed that the risk of myopathy, including rhabdomyolysis, is increased with the use of the 10 mg/80 mg dose. The risk of myopathy, including rhabdomyolysis, occurring with use of ezetimibe and simvastatin tablets is increased when taking certain types of medication or consuming grapefruit juice. Patients should discuss all medication, both prescription and over the counter, with their healthcare professional.

17.2 Liver Enzymes

It is recommended that liver function tests be performed before the initiation of ezetimibe and simvastatin tablets, and thereafter when clinically indicated. All patients treated with ezetimibe and simvastatin tablets should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.

17.3 Pregnancy

Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using ezetimibe and simvastatin tablets. Discuss future pregnancy plans with your patients, and discuss when to stop taking ezetimibe and simvastatin tablets if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking ezetimibe and simvastatin tablets and call their healthcare professional.

17.4 Breastfeeding

Women who are breastfeeding should be advised to not use ezetimibe and simvastatin tablets. Patients who have a lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professional.