11. DESCRIPTIONup
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 C24H21F2NO3 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 C25H38O5 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.
12. CLINICAL PHARMACOLOGYup
12.1 Mechanism Of Actionup
VYTORIN
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
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
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.
12.2 Pharmacodynamicsup
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.
12.3 Pharmacokineticsup
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.
Absorption
Ezetimibe
After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide).
Simvastatin
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
Ezetimibe
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.
Simvastatin
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.
Distribution
Ezetimibe
Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.
Simvastatin
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
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 14C-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
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 14C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. Plasma concentrations of total radioactivity (simvastatin plus 14C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose.
Specific Populations
Geriatric Patients
Ezetimibe
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.
Simvastatin
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).]
Gender
Ezetimibe
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.
Race
Ezetimibe
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.
Hepatic Impairment
Ezetimibe
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.
Renal Impairment
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).
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 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%).
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).]
Ezetimibe
Table 4: Effect of Coadministered Drugs on Total Ezetimibe
|
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% |
|
Statins
|
|
|
| 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% |
Table 5: Effect of Ezetimibe Coadministration on Systemic Exposure to Other Drugs
|
Coadministered Drug and its Dosage Regimen
|
Ezetimibe Dosage Regimen
|
Change in AUC
of Coadministered Drug
|
Change in Cmax
of Coadministered Drug
|
|
|
| Warfarin, 25 mg single dose on Day 7 |
10 mg QD, 11 days |
↓2% (R-warfarin) ↓4% (S-warfarin) |
↑3% (R-warfarin) ↑1% (S-warfarin) |
| 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 & Levonorgestrel
QD, 21 days |
10 mg QD,
Days 8-14 of
21 day oral contraceptive cycle |
Ethinyl estradiol
0%
Levonorgestrel 0% |
Ethinyl estradiol
↓9%
Levonorgestrel ↓5% |
| 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% |
|
Statins
|
|
|
|
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% |
Simvastatin
Table 6: Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure
|
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
|
|
|
AUC
|
Cmax
|
|
|
|
Avoid taking with VYTORIN
[see Warnings and Precautions (5.1)]
|
| Telithromycin† |
200 mg QD for 4 days |
80 mg |
simvastatin acid‡
simvastatin |
12
8.9 |
15
5.3 |
| 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 |
|
13.1 13.1 |
|
Avoid >1 quart of grapefruit juice with VYTORIN
[see Warnings and Precautions (5.1)]
|
|
Grapefruit Juice§ (high dose) |
200 mL of double-strength TID¶ |
60 mg single dose |
simvastatin acid
simvastatin |
7
16 |
|
|
Grapefruit Juice§ (low dose) |
8 oz (about 237 mL) of single-strength# |
20 mg single dose |
simvastatin acid
simvastatin |
1.3
1.9 |
|
|
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 |
2.85
1.35 |
2.18
0.91 |
|
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 |
2.3
2.5 |
2.4
2.1 |
|
No dosing adjustments required for the following:
|
| Fenofibrate |
160 mg QD x14 days |
80 mg QD on Days 8-14 |
simvastatin acid
simvastatin |
0.64
0.89 |
0.89
0.83 |
| Diltiazem |
120 mg BID for 10 days |
80 mg on Day 10 |
simvastatin acid
simvastatin |
2.69
3.10 |
2.69
2.88 |
| Amlodipine |
10 mg QD x 10 days |
80 mg on Day 10 |
simvastatin acid
simvastatin |
1.58
1.77 |
1.56
1.47 |
| Propranolol |
80 mg single dose |
80 mg single dose |
total inhibitor
active inhibitor |
0.79
0.79 |
↓ from 33.6 to 21.1 ng·eq/ml
↓ from 7.0 to 4.7 ng·eq/mL |
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HIGHLIGHTS OF PRESCRIBING INFORMATION
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These highlights do not include all the information needed to use safely and effectively. See full prescribing information for .
|
Initial U.S. Approval:
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Indications and Usage section
|
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VYTORIN®, which contains a cholesterol absorption inhibitor and an HMG-CoA reductase inhibitor (statin), is indicated as adjunctive therapy to diet to:
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FULL PRESCRIBING INFORMATION
1. INDICATIONS AND USAGEup
Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate.
1.1 Primary Hyperlipidemiaup
VYTORIN is indicated for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia.
1.2 Homozygous Familial Hypercholesterolemia (HoFH)up
VYTORIN is indicated for the reduction of elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.
1.3 Limitations of Useup
No incremental benefit of VYTORIN on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established. VYTORIN has not been studied in Fredrickson type I, III, IV, and V dyslipidemias.
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HIGHLIGHTS OF PRESCRIBING INFORMATION
|
|
These highlights do not include all the information needed to use safely and effectively. See full prescribing information for .
|
Initial U.S. Approval:
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Contraindications section
|
- Hypersensitivity to any component of this medication ( 4, 6.2)
- Active liver disease or unexplained persistent elevations of hepatic transaminase levels ( 4, 5.2)
- Women who are pregnant or may become pregnant ( 4, 8.1)
- Nursing mothers ( 4, 8.3)
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FULL PRESCRIBING INFORMATION
4. CONTRAINDICATIONSup
Hypersensitivity to any component of this medication [see Adverse Reactions (6.2)].
Active liver disease or unexplained persistent elevations in hepatic transaminase levels [see Warnings and Precautions (5.2)].
Women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins), such as simvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, VYTORIN may cause fetal harm when administered to a pregnant woman. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of VYTORIN use during pregnancy; however, in rare reports congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, simvastatin revealed no evidence of teratogenicity. VYTORIN should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, VYTORIN should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].
Nursing mothers. It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require VYTORIN treatment should not breast-feed their infants [see Use in Specific Populations (8.3)].
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
|
|
These highlights do not include all the information needed to use safely and effectively. See full prescribing information for .
|
Initial U.S. Approval:
|
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Adverse Reactions section
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- Common (incidence ≥2% and greater than placebo) adverse reactions in clinical trials: headache, increased ALT, myalgia, upper respiratory tract infection, and diarrhea. ( 6.1)
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To report SUSPECTED ADVERSE REACTIONS, contact at
or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
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FULL PRESCRIBING INFORMATION
6. ADVERSE REACTIONSup
The following serious adverse reactions are discussed in greater detail in other sections of the label:
6.1 Clinical Trials Experienceup
VYTORIN
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
In the VYTORIN (ezetimibe/simvastatin) placebo-controlled clinical trials database of 1420 patients (age range 20-83 years, 52% women, 87% Caucasians, 3% Blacks, 5% Hispanics, 3% Asians) with a median treatment duration of 27 weeks, 5% of patients on VYTORIN and 2.2% of patients on placebo discontinued due to adverse reactions.
The most common adverse reactions in the group treated with VYTORIN that led to treatment discontinuation and occurred at a rate greater than placebo were:
- Increased ALT (0.9%)
- Myalgia (0.6%)
- Increased AST (0.4%)
- Back pain (0.4%)
The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) in controlled clinical trials were: headache (5.8%), increased ALT (3.7%), myalgia (3.6%), upper respiratory tract infection (3.6%), and diarrhea (2.8%).
VYTORIN has been evaluated for safety in more than 10,189 patients in clinical trials.
Table 2 summarizes the frequency of clinical adverse reactions reported in ≥2% of patients treated with VYTORIN (n=1420) and at an incidence greater than placebo, regardless of causality assessment, from four placebo-controlled trials.
Table 2*: Clinical Adverse Reactions Occurring in ≥2% of Patients Treated with VYTORIN and at an Incidence Greater than Placebo, Regardless of Causality
Body System/Organ Class
Adverse Reaction |
Placebo
(%)
n=371 |
Ezetimibe
10 mg
(%)
n=302 |
Simvastatin†
(%)
n=1234 |
VYTORIN†
(%)
n=1420 |
|
|
|
Body as a whole – general disorders
|
|
|
|
|
| Headache |
5.4 |
6.0 |
5.9 |
5.8 |
|
Gastrointestinal system disorders
|
|
|
|
|
| Diarrhea |
2.2 |
5.0 |
3.7 |
2.8 |
|
Infections and infestations
|
|
|
|
|
| Influenza |
0.8 |
1.0 |
1.9 |
2.3 |
| Upper respiratory tract infection |
2.7 |
5.0 |
5.0 |
3.6 |
|
Musculoskeletal and connective tissue disorders
|
|
|
|
|
| Myalgia |
2.4 |
2.3 |
2.6 |
3.6 |
| Pain in extremity |
1.3 |
3.0 |
2.0 |
2.3 |
Ezetimibe
Other adverse reactions reported with ezetimibe in placebo-controlled studies, regardless of causality assessment: Musculoskeletal system disorders: arthralgia; Infections and infestations: sinusitis; Body as a whole – general disorders: fatigue.
Simvastatin
Other adverse reactions reported with simvastatin in placebo-controlled clinical studies, regardless of causality assessment: Cardiac disorders: atrial fibrillation; Ear and labyrinth disorders: vertigo; Gastrointestinal disorders: abdominal pain, constipation, dyspepsia, flatulence, gastritis; Skin and subcutaneous tissue disorders: eczema, rash; Endocrine disorders: diabetes mellitus; Infections and infestations: bronchitis, sinusitis, urinary tract infections; Body as a whole – general disorders: asthenia, edema/swelling; Psychiatric disorders: insomnia.
Laboratory Tests
Marked persistent increases of serum transaminases have been noted [see Warnings and Precautions (5.2)]. Elevated alkaline phosphatase and γ-glutamyl transpeptidase have been reported. About 5% of patients taking simvastatin had elevations of CK levels of 3 or more times the normal value on one or more occasions. This was attributable to the noncardiac fraction of CK [see Warnings and Precautions (5.1)].
6.2 Post-Marketing Experienceup
Because the below reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The following adverse reactions have been reported in post-marketing experience for VYTORIN or ezetimibe or simvastatin: pruritus; alopecia; a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails); dizziness; muscle cramps; myalgia; arthralgia; pancreatitis; memory impairment; paresthesia; peripheral neuropathy; vomiting; nausea; anemia; myopathy/rhabdomyolysis [see Warnings and Precautions (5.1)]; hepatitis/jaundice; hepatic failure; depression; cholelithiasis; cholecystitis; thrombocytopenia; elevations in liver transaminases; elevated creatine phosphokinase.
Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria have been reported.
In addition, an apparent hypersensitivity syndrome has been reported rarely that has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.
10. OVERDOSAGEup
VYTORIN
No specific treatment of overdosage with VYTORIN can be recommended. In the event of an overdose, symptomatic and supportive measures should be employed.
Ezetimibe
In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, or 40 mg/day to 18 patients with primary hyperlipidemia for up to 56 days, was generally well tolerated.
A few cases of overdosage have been reported; most have not been associated with adverse experiences. Reported adverse experiences have not been serious.
Simvastatin
Significant lethality was observed in mice after a single oral dose of 9 g/m2. No evidence of lethality was observed in rats or dogs treated with doses of 30 and 100 g/m2, respectively. No specific diagnostic signs were observed in rodents. At these doses the only signs seen in dogs were emesis and mucoid stools.
A few cases of overdosage with simvastatin have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae.
The dialyzability of simvastatin and its metabolites in man is not known at present.
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HIGHLIGHTS OF PRESCRIBING INFORMATION
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These highlights do not include all the information needed to use safely and effectively. See full prescribing information for .
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Initial U.S. Approval:
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Dosage and Administration section
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- Dosage range is 10/10 mg/day through 10/80 mg/day. ( 2.1)
- Recommended usual starting dose is 10/20 mg/day. (2.1)
- Dosing of VYTORIN should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant. ( 2.6, 7.4)
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FULL PRESCRIBING INFORMATION
2. DOSAGE AND ADMINISTRATIONup
2.1 Recommended Dosingup
The dosage range is 10/10 mg/day through 10/80 mg/day. The recommended usual starting dose is 10/20 mg/day. VYTORIN should be taken as a single daily dose in the evening, with or without food. Initiation of therapy with 10/10 mg/day may be considered for patients requiring less aggressive LDL-C reductions. Patients who require a larger reduction in LDL-C (greater than 55%) may be started at 10/40 mg/day. After initiation or titration of VYTORIN, lipid levels may be analyzed after 2 or more weeks and dosage adjusted, if needed.
2.2 Patients with Homozygous Familial Hypercholesterolemiaup
The recommended dosage for patients with homozygous familial hypercholesterolemia is VYTORIN 10/40 mg/day or 10/80 mg/day in the evening. VYTORIN should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.
2.3 Patients with Hepatic Impairmentup
No dosage adjustment is necessary in patients with mild hepatic impairment [see Warnings and Precautions (5.3)].
2.4 Patients with Renal Impairmentup
No dosage adjustment is necessary in patients with mild or moderate renal impairment. However, for patients with severe renal insufficiency, VYTORIN should not be started unless the patient has already tolerated treatment with simvastatin at a dose of 5 mg or higher. Caution should be exercised when VYTORIN is administered to these patients, and they should be closely monitored [see Warnings and Precautions (5.1); Clinical Pharmacology (12.3)].
2.5 Geriatric Patientsup
No dosage adjustment is necessary in geriatric patients [see Clinical Pharmacology (12.3)].
2.6 Coadministration with Other Drugsup
[See Warnings and Precautions (5.1) and Drug Interactions (7).]
Bile Acid Sequestrants
Dosing of VYTORIN should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant [see Drug Interactions (7.4)].
Cyclosporine or Danazol
Caution should be exercised when initiating VYTORIN in the setting of cyclosporine. In patients taking cyclosporine or danazol, VYTORIN should not be started unless the patient has already tolerated treatment with simvastatin at a dose of 5 mg or higher. The dose of VYTORIN should not exceed 10/10 mg/day [see Drug Interactions (7.5)].
Amiodarone or Verapamil
In patients taking amiodarone or verapamil concomitantly with VYTORIN, the dose should not exceed 10/20 mg/day [see Warnings and Precautions (5.1) and Drug Interactions (7.3)].
Other Concomitant Lipid-Lowering Therapy
The safety and effectiveness of VYTORIN administered with fibrates have not been established. Therefore, the combination of VYTORIN and fibrates should be avoided [see Warnings and Precautions (5.1) and Drug Interactions (7.2 and 7.7)].
There is an increased risk of myopathy when simvastatin is used concomitantly with fibrates (especially gemfibrozil). Combination therapy with gemfibrozil should be avoided because of an increase in simvastatin exposure with concomitant use. [See Warnings and Precautions (5.1) and Drug Interactions (7.2 and 7.7)].
16. HOW SUPPLIED/STORAGE AND HANDLINGup
No. 3873 — Tablets VYTORIN 10/10 are white to off-white capsule-shaped tablets with code “311” on one side.
They are supplied as follows:
NDC 66582-311-31 bottles of 30
NDC 66582-311-54 bottles of 90
NDC 66582-311-82 bottles of 1000 (If repackaged in blisters, then opaque or light-resistant blisters should be used.)
NDC 66582-311-87 bottles of 10,000 (If repackaged in blisters, then opaque or light-resistant blisters should be used.)
NDC 66582-311-28 unit dose packages of 100.
No. 3874 — Tablets VYTORIN 10/20 are white to off-white capsule-shaped tablets with code “312” on one side.
They are supplied as follows:
NDC 66582-312-31 bottles of 30
NDC 66582-312-54 bottles of 90
NDC 66582-312-82 bottles of 1000 (If repackaged in blisters, then opaque or light-resistant blisters should be used.)
NDC 66582-312-87 bottles of 10,000 (If repackaged in blisters, then opaque or light-resistant blisters should be used.)
NDC 66582-312-28 unit dose packages of 100.
No. 3875 — Tablets VYTORIN 10/40 are white to off-white capsule-shaped tablets with code “313” on one side.
They are supplied as follows:
NDC 66582-313-31 bottles of 30
NDC 66582-313-54 bottles of 90
NDC 66582-313-74 bottles of 500 (If repackaged in blisters, then opaque or light-resistant blisters should be used.)
NDC 66582-313-86 bottles of 5000 (If repackaged in blisters, then opaque or light-resistant blisters should be used.)
NDC 66582-313-52 unit dose packages of 50.
No. 3876 — Tablets VYTORIN 10/80 are white to off-white capsule-shaped tablets with code “315” on one side.
They are supplied as follows:
NDC 66582-315-31 bottles of 30
NDC 66582-315-54 bottles of 90
NDC 66582-315-74 bottles of 500 (If repackaged in blisters, then opaque or light-resistant blisters should be used.)
NDC 66582-315-66 bottles of 2500 (If repackaged in blisters, then opaque or light-resistant blisters should be used.)
NDC 66582-315-52 unit dose packages of 50.
Storage
Store at 20-25°C (68-77°F). [See USP Controlled Room Temperature.] Keep container tightly closed.
Storage of 10,000, 5000, and 2500 count bottles
Store bottle of 10,000 VYTORIN 10/10 and 10/20, 5000 VYTORIN 10/40, and 2500 VYTORIN 10/80 capsule-shaped tablets at 20-25°C (68-77°F). [See USP Controlled Room Temperature.] Store in original container until time of use. When product container is subdivided, repackage into a tightly-closed, light-resistant container. Entire contents must be repackaged immediately upon opening.
17. PATIENT COUNSELING INFORMATIONup
[See FDA-Approved Patient Labeling (17.5).]
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 VYTORIN [see Warnings and Precautions (5.1)]. Patients should also be advised to inform other physicians prescribing a new medication that they are taking VYTORIN.
17.1 Muscle Painup
All patients starting therapy with VYTORIN should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. The risk of this occurring is increased when taking certain types of medication or consuming larger quantities of grapefruit juice. They should discuss all medication, both prescription and over the counter, with their healthcare professional.
17.2 Liver Enzymesup
It is recommended that liver function tests be performed before the initiation of VYTORIN, and thereafter when clinically indicated. Patients titrated to the 10/80-mg dose should receive an additional test prior to titration, 3 months after titration to the 10/80-mg dose, and periodically thereafter (e.g., semiannually) for the first year of treatment.
17.3 Pregnancyup
Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using VYTORIN. Discuss future pregnancy plans with your patients, and discuss when to stop taking VYTORIN if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking VYTORIN and call their healthcare professional.
17.4 Breast-feedingup
Women who are breast-feeding should be advised to not use VYTORIN. Patients who have a lipid disorder and are breast-feeding should be advised to discuss the options with their healthcare professional.
17.5 FDA-Approved Patient Labelingup
Issued January 2009
9619512
Manufactured for:
MERCK/Schering-Plough Pharmaceuticals
North Wales, PA 19454, USA
By:
MSD Technology Singapore Pte. Ltd.
Singapore 637766
Or
Merck Sharp & Dohme (Italia) S.p.A.
Via Emilia, 21
27100 – Pavia, Italy
Or
Merck Sharp & Dohme Ltd.
Cramlington, Northumberland, UK NE23 3JU
Or
Jointly manufactured by:
Merck Sharp & Dohme (Italia) S.p.A.
Via Emilia, 21
27100 – Pavia, Italy
and
MSD Technology Singapore Pte. Ltd.
Singapore 637766
VYTORIN® (ezetimibe/simvastatin) Tablets
Patient Information about VYTORIN (VI-tor-in)
Generic name: ezetimibe/simvastatin tablets
Read this information carefully before you start taking VYTORIN. Review this information each time you refill your prescription for VYTORIN as there may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about VYTORIN, ask your doctor. Only your doctor can determine if VYTORIN is right for you.
What is VYTORIN?
VYTORIN contains two cholesterol-lowering medications, ezetimibe and simvastatin, available as a tablet in four strengths:
- VYTORIN 10/10 (ezetimibe 10 mg/simvastatin 10 mg)
- VYTORIN 10/20 (ezetimibe 10 mg/simvastatin 20 mg)
- VYTORIN 10/40 (ezetimibe 10 mg/simvastatin 40 mg)
- VYTORIN 10/80 (ezetimibe 10 mg/simvastatin 80 mg)
VYTORIN is a medicine used to lower levels of total cholesterol, LDL (bad) cholesterol, and fatty substances called triglycerides in the blood. In addition, VYTORIN raises levels of HDL (good) cholesterol. VYTORIN is for patients who cannot control their cholesterol levels by diet and exercise alone. You should stay on a cholesterol-lowering diet while taking this medicine.
VYTORIN works to reduce your cholesterol in two ways. It reduces the cholesterol absorbed in your digestive tract, as well as the cholesterol your body makes by itself. VYTORIN does not help you lose weight. VYTORIN has not been shown to reduce heart attacks or strokes more than simvastatin alone.
For more information about cholesterol, see the section called “What should I know about high cholesterol?”
Who should not take VYTORIN?
Do not take VYTORIN:
- If you are allergic to ezetimibe or simvastatin, the active ingredients in VYTORIN, or to the inactive ingredients. For a list of inactive ingredients, see the “Inactive ingredients” section at the end of this information sheet.
- If you have active liver disease or repeated blood tests indicating possible liver problems.
- If you are pregnant, or think you may be pregnant, or planning to become pregnant or breast-feeding.
- If you are a woman of childbearing age, you should use an effective method of birth control to prevent pregnancy while using VYTORIN.
VYTORIN has not been studied in children under 10 years of age.
What should I tell my doctor before and while taking VYTORIN?
Tell your doctor right away if you experience unexplained muscle pain, tenderness, or weakness. This is because on rare occasions, muscle problems can be serious, including muscle breakdown resulting in kidney damage.
The risk of muscle breakdown is greater at higher doses of VYTORIN.
The risk of muscle breakdown is greater in patients with kidney problems.
Taking VYTORIN with certain substances can increase the risk of muscle problems. It is particularly important to tell your doctor if you are taking any of the following:
- cyclosporine
- danazol
- antifungal agents (such as itraconazole or ketoconazole)
- fibric acid derivatives (such as gemfibrozil, bezafibrate, or fenofibrate)
- the antibiotics erythromycin, clarithromycin, and telithromycin
- HIV protease inhibitors (such as indinavir, nelfinavir, ritonavir, and saquinavir)
- the antidepressant nefazodone
- amiodarone (a drug used to treat an irregular heartbeat)
- verapamil (a drug used to treat high blood pressure, chest pain associated with heart disease, or other heart conditions)
- large doses (≥1 g/day) of niacin or nicotinic acid
- large quantities of grapefruit juice (>1 quart daily)
It is also important to tell your doctor if you are taking coumarin anticoagulants (drugs that prevent blood clots, such as warfarin).
Tell your doctor about any prescription and nonprescription medicines you are taking or plan to take, including natural or herbal remedies.
Tell your doctor about all your medical conditions including allergies.
Tell your doctor if you:
- drink substantial quantities of alcohol or ever had liver problems. VYTORIN may not be right for you.
- are pregnant or plan to become pregnant. Do not use VYTORIN if you are pregnant, trying to become pregnant or suspect that you are pregnant. If you become pregnant while taking VYTORIN, stop taking it and contact your doctor immediately.
- are breast-feeding. Do not use VYTORIN if you are breast-feeding.
Tell other doctors prescribing a new medication that you are taking VYTORIN.
How should I take VYTORIN?
Your doctor has prescribed your dose of VYTORIN. The available doses of VYTORIN are 10/10, 10/20, 10/40, and 10/80. The usual daily starting dose is VYTORIN 10/20.
- Take VYTORIN once a day, in the evening, with or without food.
- Try to take VYTORIN as prescribed. If you miss a dose, do not take an extra dose. Just resume your usual schedule.
- Continue to follow a cholesterol-lowering diet while taking VYTORIN. Ask your doctor if you need diet information.
- Keep taking VYTORIN unless your doctor tells you to stop. If you stop taking VYTORIN, your cholesterol may rise again.
What should I do in case of an overdose?
Contact your doctor immediately.
What are the possible side effects of VYTORIN?
See your doctor regularly to check your cholesterol level and to check for side effects. Your doctor may do blood tests to check your liver before you start taking VYTORIN and during treatment.
In clinical studies patients reported the following common side effects while taking VYTORIN: headache, muscle pain, and diarrhea (see What should I tell my doctor before and while taking VYTORIN?).
The following side effects have been reported in general use with VYTORIN or with ezetimibe or simvastatin tablets (tablets that contain the active ingredients of VYTORIN):
- allergic reactions including swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing (which may require treatment right away), rash, hives; joint pain; muscle pain; alterations in some laboratory blood tests; liver problems (sometimes serious); inflammation of the pancreas; nausea; dizziness; tingling sensation; depression; gallstones; inflammation of the gallbladder; trouble sleeping; poor memory.
Tell your doctor if you are having these or any other medical problems while on VYTORIN. This is not a complete list of side effects. For a complete list, ask your doctor or pharmacist.
What should I know about high cholesterol?
Cholesterol is a type of fat found in your blood. Cholesterol comes from two sources. It is produced by your body and it comes from the food you eat. Your total cholesterol is made up of both LDL and HDL cholesterol.
LDL cholesterol is called “bad” cholesterol because it can build up in the wall of your arteries and form plaque. Over time, plaque build-up can cause a narrowing of the arteries. This narrowing can slow or block blood flow to your heart, brain, and other organs. High LDL cholesterol is a major cause of heart disease and one of the causes for stroke.
HDL cholesterol is called “good” cholesterol because it keeps the bad cholesterol from building up in the arteries.
Triglycerides also are fats found in your body.
General Information about VYTORIN
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use VYTORIN for a condition for which it was not prescribed. Do not give VYTORIN to other people, even if they have the same condition you have. It may harm them.
This summarizes the most important information about VYTORIN. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about VYTORIN that is written for health professionals. For additional information, visit the following web site: vytorin.com.
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.
Issued January 2009
9619512
Manufactured for:
Merck/Schering-Plough Pharmaceuticals
North Wales, PA 19454, USA
By:
MSD Technology Singapore Pte. Ltd.
Singapore 637766
Or
Merck Sharp & Dohme (Italia) S.p.A.
Via Emilia, 21
27100 – Pavia, Italy
Or
Merck Sharp & Dohme Ltd.
Cramlington, Northumberland, UK NE23 3JU
Or
Jointly manufactured by:
Merck Sharp & Dohme (Italia) S.p.A.
Via Emilia, 21
27100 – Pavia, Italy
and
MSD Technology Singapore Pte. Ltd.
Singapore 637766