XXXXXXX
`
`VYTORIN TM 10/10
`(EZETIMIBE 10 MG/SIMVASTATIN 10 MG TABLETS)
`VYTORIN TM 10/20
`(EZETIMIBE 10 MG/SIMVASTATIN 20 MG TABLETS)
`VYTORIN TM 10/40
`(EZETIMIBE 10 MG/SIMVASTATIN 40 MG TABLETS)
`VYTORIN TM 10/80
`(EZETIMIBE 10 MG/SIMVASTATIN 80 MG TABLETS)
`
`DESCRIPTION
`
`VYTORIN contains ezetimibe, a selective inhibitor of intestinal cholesterol and related phytosterol
`absorption, and simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (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:
`
`O H
`
`O H
`
`S
`
`SR
`
`N
`
`F
`
`F
`
`O
`Simvastatin, an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form, which is an
`inhibitor of HMG-CoA 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, hydroxypropyl
`methylcellulose USP, lactose monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF,
`and propyl gallate NF.
`
`CFAD Exhibit 1047
`
`

`
`
`
`XXXXXXX
`
`VYTORIN (ezetimibe/simvastatin)
`
`CLINICAL PHARMACOLOGY
`Background
`Clinical studies have demonstrated that elevated levels of total cholesterol (total-C), low-density
`lipoprotein cholesterol (LDL-C) and apolipoprotein B (Apo B), the major protein constituent of LDL,
`promote human atherosclerosis. In addition, decreased levels of high-density lipoprotein cholesterol
`(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 very-low-
`density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote
`atherosclerosis. The independent effect of raising HDL-C or lowering triglycerides (TG) on the risk of
`coronary and cardiovascular morbidity and mortality has not been determined.
`Mode of Action
`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. 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 and appears to act 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 HMG-CoA reductase inhibitors (see CLINICAL
`STUDIES).
`
`Simvastatin
`Simvastatin reduces cholesterol by inhibiting the conversion of HMG-CoA to mevalonate, an early step
`in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces VLDL and TG and increases
`HDL-C.
`Pharmacokinetics
`Absorption
`VYTORIN
`VYTORIN is bioequivalent to coadministered ezetimibe and simvastatin.
`
`Ezetimibe
`After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically
`active phenolic glucuronide (ezetimibe-glucuronide).
`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.
`
`2
`
`

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`XXXXXXX
`
`VYTORIN (ezetimibe/simvastatin)
`
`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 slowly 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.
`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. Simvastatin undergoes extensive first-pass
`extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile.
`As a consequence of extensive hepatic extraction of simvastatin (estimated to be >60% in man), the
`availability of drug to the general circulation is low.
`Following an oral dose of 14C-labeled simvastatin in man, 13% of the dose was excreted in urine and
`60% in feces. The latter represents absorbed drug equivalents excreted in bile, as well as any unabsorbed
`drug.
`In a single-dose study in nine healthy subjects, it was estimated that less than 5% of an oral dose of
`simvastatin reaches the general circulation as active inhibitors.
`Special 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.
`
`
`3
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`XXXXXXX
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`VYTORIN (ezetimibe/simvastatin)
`
`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
`Ezetimibe
`In a multiple-dose study with ezetimibe given 10 mg once daily for 7 days, the absorption and
`metabolism of ezetimibe were similar in adolescents (10 to 18 years) and adults. Based on total ezetimibe,
`there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the
`pediatric population <10 years of age are not available.
`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 Blacks and Caucasians. There were too few patients in other racial or ethnic groups
`to permit further pharmacokinetic comparisons.
`Hepatic Insufficiency
`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 insufficiency (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 insufficiency, the mean AUC for total ezetimibe and
`ezetimibe increased approximately 4-fold compared to healthy subjects.
`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).
`
`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 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 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.
`Simvastatin is a substrate for CYP3A4. Potent inhibitors of CYP3A4 can raise the plasma levels of
`HMG-CoA reductase
`inhibitory activity and
`increase
`the risk of myopathy. (See WARNINGS,
`Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions.)
`
`4
`
`

`
`VYTORIN (ezetimibe/simvastatin)
`
`
`
`
`XXXXXXX
`
`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 study1, 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 measured
`by 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 β-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 first1 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 its
`β-hydroxyacid metabolite [measured using a chemical assay — liquid chromatography/tandem mass
`spectrometry] 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 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.
`
`1 Lilja JJ, Kivisto KT, Neuvonen PJ. Clin Pharmacol Ther 1998;64(5):477-83.
`5
`
`

`
`VYTORIN (ezetimibe/simvastatin)
`
`
`
`
`XXXXXXX
`
`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 one
`year did not result in gallstone formation or any other adverse hepatobiliary effects. In a 14-day study in
`mice given ezetimibe (0.3-5 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, 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 and
`maintained during chronic therapy.
`VYTORIN is effective in men and women with hypercholesterolemia. Experience in non-Caucasians is
`limited 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 on
`HDL-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 in
`patients with TG levels greater than or less than 200 mg/dL.
`
`
`
`
`
`
`
`
`Treatment
`
`(Daily Dose)
`Pooled data (All VYTORIN
`doses)c
`Pooled data (All simvastatin
`doses)c
`Ezetimibe 10 mg
`
`Placebo
`
`VYTORIN by dose
`
`Table 1
`Response to VYTORIN in Patients with Primary Hypercholesterolemia
`(Meana % Change from Untreated Baselineb)
`
`
`
`N
`
`609
`
`622
`
`149
`
`148
`
`
`
`152
`
`
`
`
`
`
`
`
`
`Total-C
`
`LDL-C
`
`Apo B
`
`HDL-C
`
`-38
`
`-28
`
`-13
`
`-1
`
`
`
`-31
`
`-53
`
`-39
`
`-19
`
`-2
`
`
`
`-45
`
`-42
`
`-32
`
`-15
`
`0
`
`
`
`-35
`
`+7
`
`+7
`
`+5
`
`0
`
`
`
`+8
`
`
`
`TGa
`
`-24
`
`-21
`
`-11
`
`-2
`
`
`
`-23
`
`
`
`Non-HDL-C
`
`-49
`
`-36
`
`-18
`
`-2
`
`
`
`-41
`
`10/10
`
`10/20
`
`10/40
`
`10/80
`
`Simvastatin by dose
`
`10 mg
`
`20 mg
`
`40 mg
`
`80 mg
`
`
`
`156
`
`147
`
`154
`
`
`
`158
`
`150
`
`156
`
`158
`
`-36
`
`-39
`
`-43
`
`
`
`-23
`
`-24
`
`-29
`
`-35
`
`a For triglycerides, median % change from baseline
`
`-52
`
`-55
`
`-60
`
`
`
`-33
`
`-34
`
`-41
`
`-49
`
`6
`
`-41
`
`-44
`
`-49
`
`
`
`-26
`
`-28
`
`-33
`
`-39
`
`+10
`
`+6
`
`+6
`
`
`
`+5
`
`+7
`
`+8
`
`+7
`
`-24
`
`-23
`
`-31
`
`
`
`-17
`
`-18
`
`-21
`
`-27
`
`-47
`
`-51
`
`-56
`
`
`
`-30
`
`-32
`
`-38
`
`-45
`
`

`
`VYTORIN (ezetimibe/simvastatin)
`
`
`
`
`XXXXXXX
`
`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 significantly
`increased HDL-C compared to placebo.
`
`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 VYTORIN (10/10,
`10/20, and 10/40), 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 VYTORIN 10/10, 10/20, or 10/40 were significantly larger than
`with 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
`
`253
`
`174
`
`-38
`
`251
`
`165
`
`-47
`
`109
`
`167
`
`-53
`
`97
`
`171
`
`-59
`
`
`
`N
`
`
`Mean baseline
`LDL-C
`
`Percent change
`LDL-C
`
`
`
`
`
`titration study, 788 patients with primary
`forced
`In a multicenter, double-blind, 24-week,
`hypercholesterolemia, who had not met their NCEP ATP III target LDL-C goal, were randomized to receive
`coadministered ezetimibe and simvastatin equivalent to VYTORIN (10/10 and 10/20) 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, VYTORIN lowered LDL-C to a greater degree than atorvastatin (see
`Table 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
`
`VYTORIN 10/10d
`
`VYTORIN 10/20e
`
`262
`
`263
`
`263
`
`-28
`
`-34f
`
`-36f
`
`-37
`
`-46f
`
`-50f
`
`
`
`
`
`-32
`
`-38f
`
`-41f
`
`
`
`
`
`+5
`
`+8f
`
`+10f
`
`
`
`
`
`-23
`
`-26
`
`-25
`
`
`
`
`
`-35
`
`-43f
`
`-46f
`
`Week 12
`
`Atorvastatin 20 mg
`
`VYTORIN 10/20
`
`VYTORIN 10/40
`
`Week 18
`
`Atorvastatin 40 mg
`
`VYTORIN 10/40g
`
`Week 24
`
`Atorvastatin 80 mg
`
`VYTORIN 10/80g
`
`
`
`
`
`246
`
`250
`
`252
`
`237
`
`482
`
`
`
`228
`
`459
`
`
`
`
`
`-33
`
`-37f
`
`-39f
`
`-37
`
`-40f
`
`
`
`-40
`
`-43f
`
`
`
`
`
`
`
`-38
`
`-41f
`
`-45f
`
`-42
`
`-45f
`
`
`
`-45
`
`-49f
`
`-44
`
`-50f
`
`-54f
`
`-49
`
`-56f
`
`
`
`-53
`
`-59f
`
`7
`
`
`
`+7
`
`+9
`
`+12f
`
`+8
`
`+11f
`
`
`
`+6
`
`+12f
`
`
`
`-28
`
`-28
`
`-31
`
`-31
`
`-32
`
`
`
`-35
`
`-35
`
`
`
`-42
`
`-46f
`
`-50f
`
`-47
`
`-52f
`
`
`
`-50
`
`-55f
`
`

`
`VYTORIN (ezetimibe/simvastatin)
`
`
`
`
`
`XXXXXXX
`
`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 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 VYTORIN 10/20. The median LDL-C and HbA1c levels at baseline were
`89 mg/dL and 7.1%, respectively.
`VYTORIN 10/20 was significantly more effective than doubling the dose of simvastatin to 40 mg. The
`median 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 between
`the 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%), 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 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 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. 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 on
`simvastatin 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.
`
`INDICATIONS AND USAGE
`Primary Hypercholesterolemia
`VYTORIN is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B,
`TG, and non-HDL-C, and to increase HDL-C in patients with primary (heterozygous familial and non-
`familial) hypercholesterolemia or mixed hyperlipidemia.
`Homozygous Familial Hypercholesterolemia (HoFH)
`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.
`Therapy with lipid-altering agents should be a component of multiple risk-factor intervention in
`individuals at increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Lipid-
`altering agents should be used in addition to an appropriate diet (including restriction of saturated fat and
`
`8
`
`

`
`VYTORIN (ezetimibe/simvastatin)
`
`cholesterol) and when the response to diet and other non-pharmacological measures has been
`inadequate. (See NCEP Adult Treatment Panel (ATP) III Guidelines, summarized in Table 4.)
`
`
`
`
`XXXXXXX
`
`Risk Category
`
`CHD or CHD risk equivalentsb
`(10-year risk >20%)c
`
`2+ Risk factorse
`(10-year risk ≤20%)c
`
`0-1 Risk factorf
`
`Table 4
`Summary of NCEP ATP III Guidelines
`
`LDL Level at Which to Initiate
`Therapeutic Lifestyle Changesa
`(mg/dL)
`
`LDL Goal
`(mg/dL)
`
`<100
`
`<130
`
`<160
`
`≥100
`
`≥130
`
`≥160
`
`LDL level at Which to
`Consider Drug Therapy
`(mg/dL)
`
`≥130
`(100-129: drug optional)d
`
`10-year risk 10-20%: ≥130c
`10-year risk <10%: ≥160c
`≥190
`(160-189: LDL-lowering drug
`optional)
`
`
`
`
`
`a Therapeutic lifestyle changes include: 1) dietary changes: reduced intake of saturated fats (<7% of total calories) and cholesterol
`(<200 mg per day), and enhancing LDL lowering with plant stanols/sterols (2 g/d) and increased viscous (soluble) fiber (10-25 g/d),
`2) weight reduction, and 3) increased physical activity.
`b CHD risk equivalents comprise: diabetes, multiple risk factors that confer a 10-year risk for CHD >20%, and other clinical forms of
`atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm and symptomatic carotid artery disease).
`c Risk assessment for determining the 10-year risk for developing CHD is carried out using the Framingham risk scoring. Refer to JAMA,
`May 16, 2001; 285 (19): 2486-2497, or the NCEP website (http://www.nhlbi.nih.gov) for more details.
`d Some authorities recommend use of LDL-lowering drugs in this category if an LDL cholesterol <100 mg/dL cannot be achieved by
`therapeutic lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL, e.g., nicotinic acid or fibrate.
`Clinical judgment also may call for deferring drug therapy in this subcategory.
`e Major risk factors (exclusive of LDL cholesterol) that modify LDL goals include cigarette smoking, hypertension (BP ≥140/90 mm Hg or
`on anti-hypertensive medication), low HDL cholesterol (<40 mg/dL), family history of premature CHD (CHD in male first-degree relative
`<55 years; CHD in female first-degree relative <65 years), age (men ≥45 years; women ≥55 years). HDL cholesterol ≥60 mg/dL counts
`as a “negative” risk factor; its presence removes one risk factor from the total count.
`f Almost all people with 0-1 risk factor have a 10-year risk <10%; thus, 10-year risk assessment in people with 0-1 risk factor is not
`necessary.
`
`Prior to initiating therapy with VYTORIN, secondary causes for dyslipidemia (i.e., diabetes,
`hypothyroidism, obstructive liver disease, chronic renal failure, and drugs that increase LDL-C and
`decrease HDL-C [progestins, anabolic steroids, and corticosteroids]), should be excluded or, if
`appropriate, treated. A lipid profile should be performed to measure total-C, LDL-C, HDL-C and TG. For
`TG levels >400 mg/dL (>4.5 mmol/L), LDL-C concentrations should be determined by ultracentrifugation.
`At the time of hospitalization for an acute coronary event, lipid measures should be taken on admission
`or within 24 hours. These values can guide the physician on initiation of LDL-lowering therapy before or at
`discharge.
`
`CONTRAINDICATIONS
`
`Hypersensitivity to any component of this medication.
`
`Active liver disease or unexplained persistent elevations in serum transaminases (see WARNINGS,
`Liver Enzymes).
`
`Pregnancy and lactation. 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. Moreover, cholesterol and other products of the cholesterol biosynthesis pathway
`are essential components for fetal development, including synthesis of steroids and cell membranes.
`Because of the ability of inhibitors of HMG-CoA reductase such as simvastatin to decrease the synthesis
`of cholesterol and possibly other products of the cholesterol biosynthesis pathway, VYTORIN is
`contraindicated during pregnancy and in nursing mothers. VYTORIN should be administered to women
`of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes
`
`9
`
`

`
`VYTORIN (ezetimibe/simvastatin)
`
`pregnant while taking this drug, VYTORIN should be discontinued immediately and the patient should be
`apprised of the potential hazard to the fetus (see PRECAUTIONS, Pregnancy).
`
`XXXXXXX
`
`
`
`WARNINGS
`Myopathy/Rhabdomyolysis
`In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with ezetimibe
`compared with the relevant control arm (placebo or HMG-CoA reductase inhibitor alone). However,
`m