Ezetimibe and Simvastatin (Page 9 of 11)

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 to 80 mg (n=5) produced a reduction of LDL-C of 13% from baseline on simvastatin 40 mg. Co-administered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin (10/40 and 10/80 pooled, n=9), produced a reduction of LDL-C of 23% from baseline on simvastatin 40 mg. In those patients co-administered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin (10/80, 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 9,438 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 10/20, 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 10/20 or placebo. A total of 9,270 patients were ever allocated to ezetimibe and simvastatin 10/20 (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 m2 , with 94% of patients having an eGFR < 45 mL/min/1.73m2. 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 4,620 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 10/20 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).

Figure 1: Effect of E zetimibe and Simvastatin on the Primary Endpoint of Risk of Major Vascular Events

1
(click image for full-size original)

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*

Outcome

Ezetimibe and simvastatin 10/20

(N=4,650)

Placebo

(N=4,620)

Risk Ratio

(95% CI)

P-value

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

* Intention-to-treat analysis on all SHARP patients ever allocated to ezetimibe and simvastatin or placebo.

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).

16 HOW SUPPLIED/STORAGE AND HANDLING

Ezetimibe and simvastatin tablets, 10/10 mg , are supplied as white to off-white, capsule shaped tablets, debossed with “AA 70” on one side and plain on the other side.

They are available as follows:

Bottles of 30: NDC 69238-1155-3

Bottles of 90: NDC 69238-1155-9

Ezetimibe and simvastatin tablets, 10/20 mg , are supplied as white to off-white, capsule shaped tablets, debossed with “AA 71” on one side and plain on the other side.

They are available as follows:

Bottles of 30: NDC 69238-1156-3

Bottles of 90: NDC 69238-1156-9

Ezetimibe and simvastatin tablets, 10/40 mg , are supplied as white to off-white, capsule shaped tablets, debossed with “AA 72” on one side and plain on the other side.

They are available as follows:

Bottles of 30: NDC 69238-1157-3

Bottles of 90: NDC 69238-1157-9

Ezetimibe and simvastatin tablets, 10/80 mg , are supplied as white to off-white, capsule shaped tablets, debossed with “AA 73” on one side and plain on the other side.

They are available as follows:

Bottles of 30: NDC 69238-1158-3

Bottles of 90: NDC 69238-1158-9

Storage

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Keep container tightly closed.

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