VYTORIN contains ezetimibe, a selective inhibitor of intestinal cholesterol and related phytosterol absorption, and simvastatin, an HMG-CoA reductase inhibitor.
The chemical name of ezetimibe is 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. The empirical formula is C24 H21 F2 NO3 and its molecular weight is 409.4.
Ezetimibe is a white, crystalline powder that is freely to very soluble in ethanol, methanol, and acetone and practically insoluble in water. Its structural formula is:
Simvastatin, an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form, which is an inhibitor of HMGCoA reductase. Simvastatin is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H -pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S -[1α,3α,7β,8β(2S* ,4S*),-8aβ]]. The empirical formula of simvastatin is C25 H38 O5 and its molecular weight is 418.57.
Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water and freely soluble in chloroform, methanol and ethanol. Its structural formula is:
VYTORIN is available for oral use as tablets containing 10 mg of ezetimibe, and 10 mg of simvastatin (VYTORIN 10/10), 20 mg of simvastatin (VYTORIN 10/20), 40 mg of simvastatin (VYTORIN 10/40), or 80 mg of simvastatin (VYTORIN 10/80). Each tablet contains the following inactive ingredients: butylated hydroxyanisole NF, citric acid monohydrate USP, croscarmellose sodium NF, hypromellose USP, lactose monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF, and propyl gallate NF.
Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. VYTORIN contains ezetimibe and simvastatin, two lipid-lowering compounds with complementary mechanisms of action. VYTORIN reduces elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and increases HDL-C through dual inhibition of cholesterol absorption and synthesis.
Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. In a 2-week clinical study in 18 hypercholesterolemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and E and did not impair adrenocortical steroid hormone production.
Ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood; this distinct mechanism is complementary to that of statins [see Clinical Studies (14)].
Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces very-low-density lipoproteins (VLDL) and TG and increases HDL-C.
Clinical studies have demonstrated that elevated levels of total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. The independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.
The results of a bioequivalence study in healthy subjects demonstrated that the VYTORIN (ezetimibe/simvastatin) 10 mg/10 mg to 10 mg/80 mg combination tablets are bioequivalent to coadministration of corresponding doses of ezetimibe (ZETIA®) and simvastatin (ZOCOR®) as individual tablets.
After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide).
The availability of the β-hydroxyacid to the systemic circulation following an oral dose of simvastatin was found to be less than 5% of the dose, consistent with extensive hepatic first-pass extraction.
Effect of Food on Oral Absorption
Concomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as 10-mg tablets. The Cmax value of ezetimibe was increased by 38% with consumption of high-fat meals.
Relative to the fasting state, the plasma profiles of both active and total inhibitors of HMG-CoA reductase were not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal.
Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.
Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. When radiolabeled simvastatin was administered to rats, simvastatin-derived radioactivity crossed the blood-brain barrier.
Metabolism and Excretion
Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation with subsequent biliary and renal excretion. Minimal oxidative metabolism has been observed in all species evaluated.
In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling.
Following oral administration of 14 C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, there were no detectable levels of radioactivity in the plasma.
Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose.
Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is a basis for an assay in pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of simvastatin. The major active metabolites of simvastatin present in human plasma are the β-hydroxyacid of simvastatin and its 6′-hydroxy, 6′-hydroxymethyl, and 6′-exomethylene derivatives.
Following an oral dose of 14 C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. Plasma concentrations of total radioactivity (simvastatin plus 14 C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose.
In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were about 2-fold higher in older (≥65 years) healthy subjects compared to younger subjects.
In a study including 16 elderly patients between 70 and 78 years of age who received simvastatin 40 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18-30 years of age.
Pediatric Patients: [See Pediatric Use (8.4).]
In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (<20%) in women than in men.
Based on a meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Black and Caucasian subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe was similar to those seen in Caucasian subjects.
After a single 10-mg dose of ezetimibe, the mean exposure (based on area under the curve [AUC]) to total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic impairment (Child-Pugh score 5 to 6), compared to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe increased approximately 3- to 4-fold and 5- to 6-fold, respectively, in patients with moderate (Child-Pugh score 7 to 9) or severe hepatic impairment (Child-Pugh score 10 to 15). In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic impairment, the mean AUC for total ezetimibe and ezetimibe increased approximately 4-fold compared to healthy subjects.
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).
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 in patients with severe renal impairment (as measured by creatinine clearance).
Drug Interactions [See also Drug Interactions (7).]
No clinically significant pharmacokinetic interaction was seen when ezetimibe was coadministered with simvastatin. No specific pharmacokinetic drug interaction studies with VYTORIN have been conducted other than the following study with NIASPAN (Niacin extended-release tablets).
Niacin: The effect of VYTORIN (10/20 mg daily for 7 days) on the pharmacokinetics of NIASPAN extended-release tablets (1000 mg for 2 days and 2000 mg for 5 days following a low-fat breakfast) was studied in healthy subjects. The mean Cmax and AUC of niacin increased 9% and 22%, respectively. The mean Cmax and AUC of nicotinuric acid increased 10% and 19%, respectively (N=13). In the same study, the effect of NIASPAN on the pharmacokinetics of VYTORIN was evaluated (N=15). While concomitant NIASPAN decreased the mean Cmax of total ezetimibe (1%), and simvastatin (2%), it increased the mean Cmax of simvastatin acid (18%). In addition, concomitant NIASPAN increased the mean AUC of total ezetimibe (26%), simvastatin (20%), and simvastatin acid (35%).
Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. [See Warnings and Precautions (5.1) and Drug Interactions (7.4).]
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 of the 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.
Although the mechanism is not fully understood, cyclosporine has been shown to increase the AUC of statins. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4.
Simvastatin is a substrate for CYP3A4. Inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy. [See Warnings and Precautions (5.1); Drug Interactions (7.1).]
|Coadministered Drug and Dosing Regimen||Total Ezetimibe *|
|Change in AUC||Change in Cmax|
|Cyclosporine-stable dose required (75-150 mg BID)†, ‡||↑240%||↑290%|
|Fenofibrate, 200 mg QD, 14 days ‡||↑48%||↑64%|
|Gemfibrozil, 600 mg BID, 7 days ‡||↑64%||↑91%|
|Cholestyramine, 4 g BID, 14 days ‡||↓55%||↓4%|
|Aluminum & magnesium hydroxide combination antacid, single dose §||↓4%||↓30%|
|Cimetidine, 400 mg BID, 7 days||↑6%||↑22%|
|Glipizide, 10 mg, single dose||↑4%||↓8%|
|Lovastatin 20 mg QD, 7 days||↑9%||↑3%|
|Pravastatin 20 mg QD, 14 days||↑7%||↑23%|
|Atorvastatin 10 mg QD, 14 days||↓2%||↑12%|
|Rosuvastatin 10 mg QD, 14 days||↑13%||↑18%|
|Fluvastatin 20 mg QD, 14 days||↓19%||↑7%|
|Coadministered Drug and its Dosage Regimen||Ezetimibe Dosage Regimen|| |
Change in AUCof Coadministered Drug
Change in Cmaxof Coadministered Drug
|Warfarin, 25 mg single dose on Day 7||10 mg QD, 11 days|| |
|Digoxin, 0.5 mg single dose||10 mg QD, 8 days||↑2%||↓7%|
|Gemfibrozil, 600 mg BID, 7 days *||10 mg QD, 7 days||↓1%||↓11%|
|Ethinyl estradiol & LevonorgestrelQD, 21 days||10 mg QD,Days 8-14 of21 day oral contraceptive cycle|| |
|Glipizide, 10 mg on Days 1 and 9||10 mg QD, Days 2-9||↓3%||↓5%|
|Fenofibrate, 200 mg QD, 14 days *||10 mg QD, 14 days||↑11%||↑7%|
|Cyclosporine, 100 mg single dose Day 7*||20 mg QD, 8 days||↑15%||↑10%|
|Lovastatin 20 mg QD, 7 days||10 mg QD, 7 days||↑19%||↑3%|
|Pravastatin 20 mg QD, 14 days||10 mg QD, 14 days||↓20%||↓24%|
|Atorvastatin 10 mg QD, 14 days||10 mg QD, 14 days||↓4%||↑7%|
|Rosuvastatin 10 mg QD, 14 days||10 mg QD, 14 days||↑19%||↑17%|
|Fluvastatin 20 mg QD, 14 days||10 mg QD, 14 days||↓39%||↓27%|
|Coadministered Drug or Grapefruit Juice||Dosing of Coadministered Drug or Grapefruit Juice||Dosing of Simvastatin|| |
Geometric Mean Ratio
(Ratio * with / without coadministered drug)No Effect = 1.00
|Avoid taking with VYTORIN [see Warnings and Precautions (5.1)]|
|Telithromycin †||200 mg QD for 4 days||80 mg||simvastatin acid ‡ simvastatin||128.9||155.3|
|Nelfinavir †||1250 mg BID for 14 days||20 mg QD for 28 days||simvastatin acid ‡ simvastatin||6||6.2|
|Itraconazole †||200 mg QD for 4 days||80 mg||simvastatin acid ‡ simvastatin|| |
|Avoid >1 quart of grapefruit juice with VYTORIN [see Warnings and Precautions (5.1)]|
Grapefruit Juice §
|200 mL of double-strength TID ¶||60 mg single dose||simvastatin acid simvastatin||716|
Grapefruit Juice §
|8 oz (about 237 mL) of single-strength #||20 mg single dose||simvastatin acid simvastatin||1.31.9|
|Avoid taking with VYTORIN. If VYTORIN is used in combination with gemfibrozil, the dose should not exceed 10/10 mg daily , based on clinical and/or post-marketing simvastatin experience [see Warnings and Precautions (5.1)]|
|Gemfibrozil||600 mg BID for 3 days||40 mg||simvastatin acid simvastatin||2.851.35||2.180.91|
|Avoid taking with >10/20 mg VYTORIN , based on clinical and/or post-marketing simvastatin experience [see Warnings and Precautions (5.1)]|
|Verapamil SR||240 mg QD Days 1-7 then 240 mg BID on Days 8-10||80 mg on Day 10||simvastatin acid simvastatin||2.32.5||2.42.1|
|Avoid taking with >10/40 mg VYTORIN , based on clinical and/or post-marketing simvastatin experience [see Warnings and Precautions (5.1)]|
|Diltiazem||120 mg BID for 10 days||80 mg on Day 10||simvastatin acid simvastatin||2.693.10||2.692.88|
|Diltiazem||120 mg BID for 14 days||20 mg on Day 14||simvastatin||4.6||3.6|
|No dosing adjustments required for the following:|
|Fenofibrate||160 mg QD x14 days||80 mg QD on Days 8-14||simvastatin acid simvastatin||0.640.89||0.890.83|
|Amlodipine||10 mg QD x 10 days||80 mg on Day 10||simvastatin acid simvastatin||1.581.77||1.561.47|
|Propranolol||80 mg single dose||80 mg single dose||total inhibitor active inhibitor||0.790.79||↓ from 33.6 to 21.1 ng·eq/ml↓ from 7.0 to 4.7 ng·eq/mL|
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