Vytorin

[ezetimibe/simvastatin]

Renal Insufficiency

Ezetimibe

After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl=30 mL/min/1.73 m2), the mean AUC for total ezetimibe and ezetimibe increased approximately 1.5-fold,compared to healthy subjects (n=9).

Text Continues Below

---

Simvastatin

Pharmacokinetic studies with another statin having a similar principal route of elimination to that of simvastatin have suggested that for a given dose level higher systemic exposure may be achieved inpatients with severe renal insufficiency (as measured by creatinine clearance).

Drug Interactions (See also PRECAUTIONS, Drug Interactions)

No clinically significant pharmacokinetic interaction was seen when ezetimibe was coadministered with simvastatin. Specific pharmacokinetic drug interaction studies with VYTORIN have not been performed.

Cytochrome P450:

Ezetimibe had no significant effect on a series of probe drugs (caffeine,dextromethorphan, tolbutamide, and IV midazolam) known to be metabolized by cytochrome P450 (1A2,2D6, 2C8/9 and 3A4) in a "cocktail" study of twelve healthy adult males. This indicates that ezetimibe is neither an inhibitor nor an inducer of these cytochrome P450 isozymes, and it is unlikely that ezetimibe will affect the metabolism of drugs that are metabolized by these enzymes. In a study of 12 healthy volunteers, simvastatin at the 80-mg dose had no effect on the metabolism ofthe probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates that simvastatin is not an inhibitor of CYP3A4, and, therefore, is not expected to affect the plasma levels of other drugs metabolized by CYP3A4. Simvastatin is a substrate for CYP3A4. Potent inhibitors of CYP3A4 can raise the plasma levels ofHMG-CoA reductase inhibitory activity and increase the risk of myopathy. (See WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions.)

Antacids:

In a study of twelve healthy adults, a single dose of antacid (SupraloxTM 20 mL) administration had no significant effect on the oral bioavailability of total ezetimibe, ezetimibe-glucuronide, or ezetimibe based on AUC values. The Cmax value of total ezetimibe was decreased by 30%.

Cholestyramine:

In a study of forty healthy hypercholesterolemic (LDL-C =130 mg/dL) adult subjects, concomitant cholestyramine (4 g twice daily) administration decreased the mean AUC of total ezetimibe and ezetimibe approximately 55% and 80%, respectively.

Cyclosporine:

In a study of eight post-renal transplant patients with mildly impaired or normal renal function (creatinine clearance of >50 mL/min), stable doses of cyclosporine (75 to 150 mg twice daily) increased the mean AUC and Cmax values of total ezetimibe 3.4-fold (range 2.3- to 7.9-fold) and 3.9-fold (range 3.0- to 4.4-fold), respectively, compared to a historical healthy control population (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects.

Fenofibrate:

In a study of thirty-two healthy hypercholesterolemic (LDL-C =130 mg/dL) adult subjects, concomitant fenofibrate (200 mg once daily) administration increased the mean Cmax and AUC values of total ezetimibe approximately 64% and 48%, respectively. Pharmacokinetics of fenofibrate were not significantly affected by ezetimibe (10 mg once daily).

Gemfibrozil:

In a study of twelve healthy adult males, concomitant administration of gemfibrozil (600 mg twice daily) significantly increased the oral bioavailability of total ezetimibe by a factor of 1.7. Ezetimibe (10 mg once daily) did not significantly affect the bioavailability of gemfibrozil.

Grapefruit Juice:

Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the plasma concentrations of drugs metabolized by CYP3A4. In one study, 10 subjects consumed 200 mL of double-strength grapefruit juice (one can of frozen concentrate diluted with one rather than 3 cans of water) three times daily for 2 days and an additional 200 mL double-strength grapefruit juice together with, and 30 and 90 minutes following, a single dose of 60 mg simvastatin on the third day. This regimen of grapefruit juice resulted in mean increases in the concentration (as measuredby the area under the concentration-time curve) of active and total HMG-CoA reductase inhibitory activity [measured using a radioenzyme inhibition assay both before (for active inhibitors) and after (for total inhibitors) base hydrolysis] of 2.4-fold and 3.6-fold, respectively, and of simvastatin and its ß-hydroxyacid metabolite [measured using a chemical assay - liquid chromatography/tandem mass spectrometry] of 16-fold and 7-fold, respectively.

In a second study, 16 subjects consumed one 8 oz glass of single strength grapefruit juice (one can of frozen concentrate diluted with 3 cans of water) with breakfast for 3 consecutive days and a single dose of 20 mg simvastatin in the evening of the third day. This regimen of grapefruit juice resulted in a mean increase in the plasma concentration (as measured by the area under the concentration-time curve) of active and total HMG-CoA reductase inhibitory activity [using a validated enzyme inhibition assay different from that used in the first study, both before (for active inhibitors) and after (for total inhibitors) base hydrolysis] of 1.13-fold and 1.18-fold, respectively, and of simvastatin and itsß-hydroxyacid metabolite [measured using a chemical assay - liquid chromatography/tandem masss pectrometry] of 1.88-fold and 1.31-fold, respectively. The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied.

ANIMAL PHARMACOLOGY

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 µg/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 µg/kg/day, respectively. These results are consistent with ezetimibe being apotent cholesterol absorption inhibitor. In a rat model, where the glucuronide metabolite of ezetimibe (ezetimibe-glucuronide) wasadministered intraduodenally, the metabolite was as potent as ezetimibe in inhibiting the absorption ofcholesterol, suggesting that the glucuronide metabolite had activity similar to the parent drug.1 Lilja JJ, Kivisto KT, Neuvonen PJ. Clin Pharmacol Ther 1998;64(5):477-83.

In 1-month studies in dogs given ezetimibe (0.03-300 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 oneyear did not result in gallstone formation or any other adverse hepatobiliary effects. In a 14-day study in mice given ezetimibe (0.3-5 mg/kg/day) and fed a low-fat or cholesterol-rich diet, the concentration of cholesterol in gall bladder 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, ethyl 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 HMG-CoA reductase inhibitors (parents or their active hydroxy acid metabolites) was seen in rats, dogs, and rabbits.

CLINICAL STUDIES

Primary Hypercholesterolemia

VYTORIN

VYTORIN reduces total-C, LDL-C, Apo B, TG, and non-HDL-C, and increases HDL-C in patients with hypercholesterolemia. Maximal to near maximal response is generally achieved within 2 weeks andmaintained during chronic therapy. VYTORIN is effective in men and women with hypercholesterolemia. Experience in non-Caucasians islimited and does not permit a precise estimate of the magnitude of the effects of VYTORIN. In a multicenter, double-blind, placebo-controlled, 12-week trial, 1528 hypercholesterolemic patients were randomized to one of ten treatment groups: placebo, ezetimibe (10 mg), simvastatin (10 mg, 20 mg,40 mg, or 80 mg), or VYTORIN (10/10, 10/20, 10/40, or 10/80). When patients receiving VYTORIN were compared to those receiving all doses of simvastatin, VYTORIN significantly lowered total-C, LDL-C, Apo B, TG, and non-HDL-C. The effects of VYTORIN onHDL-C were similar to the effects seen with simvastatin. Further analysis showed VYTORIN significantly increased HDL-C compared with placebo. (See Table 1.) The lipid response to VYTORIN was similar inpatients with TG levels greater than or less than 200 mg/dL.

Table 1
Response to VYTORIN in Patients with Primary Hypercholesterolemia
(Mean a % Change from Untreated Baseline b)
Treatment
(Daily Dose) N Total-C LDL-C Apo B HDL-C TGa Non-HDL-C
Pooled data (All VYTORIN
doses)c 609 -38 -53 -42 +7 -24 -49
Pooled data (All simvastatin
doses)c
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
VYTORIN 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
a For triglycerides, median % change from baseline
b Baseline - on no lipid-lowering drug
c VYTORIN doses pooled (10/10-10/80) significantly reduced total-C, LDL-C, Apo B, TG, and non-HDL-C compared to simvastatin, and significantlyincreased HDL-C compared to placebo.In a multicenter, double-blind, controlled, 23-week study, 710 patients with known CHD or CHD riskequivalents, as defined by the NCEP ATP III guidelines, and an LDL-C =130 mg/dL were randomized toone of four treatment groups: coadministered ezetimibe and simvastatin equivalent to VYTORIN (10/10,10/20, and 10/40), or simvastatin 20 mg. Patients not reaching an LDL-C <100 mg/dL had theirsimvastatin dose titrated at 6-week intervals to a maximal dose of 80 mg.At Week 5, the LDL-C reductions with VYTORIN 10/10, 10/20, or 10/40 were significantly larger thanwith simvastatin 20 mg (see Table 2).Table 2

Response to VYTORIN after 5 Weeks in Patients with CHD or CHD Risk Equivalents
and an LDL-C =130 mg/dL
Simvastatin
20 mg
VYTORIN
10/10
VYTORIN
10/20
VYTORIN
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, 24-week, forced titration study, 788 patients with primaryhypercholesterolemia, who had not met their NCEP ATP III target LDL-C goal, were randomized to receivecoadministered ezetimibe and simvastatin equivalent to VYTORIN (10/10 and 10/20) or atorvastatin10 mg. For all three treatment groups, the dose of the statin was titrated at 6-week intervals to 80 mg. Ateach pre-specified dose comparison, VYTORIN lowered LDL-C to a greater degree than atorvastatin (seeTable 3).

Table 3
Response to VYTORIN and Atorvastatin in Patients with Primary Hypercholesterolemia
(Meana % Change from Untreated Baselineb)
Treatment N Total-C LDL-C Apo B HDL-C TGa Non-HDL-C
Week 6
Atorvastatin 10 mgc 262 -28 -37 -32 +5 -23 -35
VYTORIN 10/10d 263 -34f -46f -38f +8f -26 -43f
VYTORIN 10/20e 263 -36f -50f -41f +10f -25 -46f
Week 12
Atorvastatin 20 mg 246 -33 -44 -38 +7 -28 -42
VYTORIN 10/20 250 -37f -50f -41f +9 -28 -46f
VYTORIN 10/40 252 -39f -54f -45f +12f -31 -50f
Week 18
Atorvastatin 40 mg 237 -37 -49 -42 +8 -31 -47
VYTORIN 10/40g 482 -40f -56f -45f +11f -32 -52f
Week 24
Atorvastatin 80 mg 228 -40 -53 -45 +6 -35 -50
VYTORIN 10/80g 459 -43f -59f -49f +12f -35 -55f

a For triglycerides, median % change from baseline
b Baseline - on no lipid-lowering drug
c Atorvastatin: 10 mg start dose titrated to 20 mg, 40 mg, and 80 mg through Weeks 6, 12, 18, and 24
d VYTORIN: 10/10 start dose titrated to 10/20, 10/40, and 10/80 through Weeks 6, 12, 18, and 24
e VYTORIN: 10/20 start dose titrated to 10/40, 10/40, and 10/80 through Weeks 6, 12, 18, and 24
f p=0.05 for difference with atorvastatin in the specified week
g Data pooled for common doses of VYTORIN at Weeks 18 and 24.

In a multicenter, double-blind, 24-week trial, 214 patients with type 2 diabetes mellitus treated withthiazolidinediones (rosiglitazone or pioglitazone) for a minimum of 3 months and simvastatin 20 mg for aminimum of 6 weeks, were randomized to receive either simvastatin 40 mg or the coadministered activeingredients equivalent to VYTORIN 10/20. The median LDL-C and HbA1c levels at baseline were89 mg/dL and 7.1%, respectively.VYTORIN 10/20 was significantly more effective than doubling the dose of simvastatin to 40 mg. Themedian percent changes from baseline for VYTORIN 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 betweenthe two treatment groups were not significantly different.

Ezetimibe

In two multicenter, double-blind, placebo-controlled, 12-week studies in 1719 patients with primary hypercholesterolemia, ezetimibe significantly lowered total-C (-13%), LDL-C (-19%), Apo B (-14%), andTG (-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=4,444patients) 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 VYTORIN on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established. Homozygous Familial Hypercholesterolemia (HoFH)A double-blind, randomized, 12-week study was performed in patients with a clinical and/or genotypicdiagnosis 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. Coadministered ezetimibe and simvastatin equivalent to VYTORIN (10/40 and 10/80 pooled, n=9), produced a reduction of LDL-C of 23% from baseline onsimvastatin 40 mg. In those patients coadministered ezetimibe and simvastatin equivalent to VYTORIN(10/80, n=5), a reduction of LDL-C of 29% from baseline on simvastatin 40 mg was produced.

Page:  << Prev | 1 | 2 | 3 | 4 | 5