7825441
`
`TABLETS
`ZOCOR®
`(SIMVASTATIN)
`
`DESCRIPTION
`ZOCOR* (simvastatin) is a lipid-lowering agent that is derived synthetically from a fermentation product
`of Aspergillus terreus. After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed to the
`corresponding β-hydroxyacid form. This is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A
`(HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an
`early and rate-limiting step in the biosynthesis of cholesterol.
`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. Its structural formula is:
`
`Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in
`water, and freely soluble in chloroform, methanol and ethanol.
`Tablets ZOCOR for oral administration contain either 5 mg, 10 mg, 20 mg, 40 mg or 80 mg of
`simvastatin and the following inactive ingredients: cellulose, hydroxypropyl cellulose, hydroxypropyl
`methylcellulose, iron oxides, lactose, magnesium stearate, starch, talc, titanium dioxide and other
`ingredients. Butylated hydroxyanisole is added as a preservative.
`
`CLINICAL PHARMACOLOGY
`The involvement of low-density lipoprotein cholesterol (LDL-C) in atherogenesis has been well-
`documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological
`studies have established that high LDL-C, low high-density lipoprotein cholesterol (HDL-C), and high
`plasma triglycerides (TG) are risk factors for coronary heart disease (CHD). Cholesterol-enriched TG-rich
`lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and
`remnants, can also promote atherosclerosis. Elevated plasma TG are frequently found in a triad with low
`HDL-C and small LDL particles, as well as in association with non-lipid metabolic risk factors for CHD. As
`such, total plasma TG has not consistently been shown to be an independent risk factor for CHD.
`Furthermore, the independent effect of raising HDL-C or lowering TG on the risk of coronary and
`cardiovascular morbidity and mortality has not been determined.
`In the Scandinavian Simvastatin Survival Study (4S), the effect of improving lipoprotein levels with
`ZOCOR on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol (total-C)
`212-309 mg/dL (5.5-8.0 mmol/L). The patients were followed for a median of 5.4 years. In this multicenter,
`randomized, double-blind, placebo-controlled study, ZOCOR significantly reduced the risk of mortality by
`30% (11.5% vs 8.2%, placebo vs ZOCOR); of CHD mortality by 42% (8.5% vs 5.0%); and of having a
`hospital-verified non-fatal myocardial infarction by 37% (19.6% vs 12.9%). Furthermore, ZOCOR
`
`* Registered trademark of MERCK & CO., Inc.
`COPYRIGHT © MERCK & CO., Inc., 1991, 1995, 1998
`All rights reserved
`
`CFAD Exhibit 1048
`
`

`
`ZOCOR® (simvastatin)
`
`7825441
`
`significantly reduced the risk for undergoing myocardial revascularization procedures (coronary artery
`bypass grafting or percutaneous transluminal coronary angioplasty) by 37% (17.2% vs 11.4%) [see
`CLINICAL PHARMACOLOGY, Clinical Studies].
`ZOCOR has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed
`from very-low-density lipoprotein (VLDL) and is catabolized predominantly by the high-affinity LDL
`receptor. The mechanism of the LDL-lowering effect of ZOCOR may involve both reduction of VLDL
`cholesterol concentration, and induction of the LDL receptor, leading to reduced production and/or
`increased catabolism of LDL-C. Apolipoprotein B (Apo B) also falls substantially during treatment with
`ZOCOR. As each LDL particle contains one molecule of Apo B, and since in patients with predominant
`elevations in LDL-C (without accompanying elevation in VLDL) little Apo B is found in other lipoproteins,
`this strongly suggests that ZOCOR does not merely cause cholesterol to be lost from LDL, but also
`reduces the concentration of circulating LDL particles. In addition, ZOCOR reduces VLDL and TG and
`increases HDL-C. The effects of ZOCOR on Lp(a), fibrinogen, and certain other independent biochemical
`risk markers for CHD are unknown.
`ZOCOR is a specific inhibitor of HMG-CoA reductase, the enzyme that catalyzes the conversion of
`HMG-CoA to mevalonate. The conversion of HMG-CoA to mevalonate is an early step in the biosynthetic
`pathway for cholesterol.
`Pharmacokinetics
`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 the 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.
`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. 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. Absorption of simvastatin, estimated
`relative to an intravenous reference dose, in each of two animal species tested, averaged about 85% of an
`oral dose. In animal studies, after oral dosing, simvastatin achieved substantially higher concentrations in
`the liver than in non-target tissues. 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. 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. Following
`administration of simvastatin tablets, the coefficient of variation, based on between-subject variability, was
`approximately 48% for the area under the concentration-time curve (AUC) for total inhibitory activity in the
`general circulation.
`Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human
`plasma proteins. Animal studies have not been performed to determine whether simvastatin crosses the
`blood-brain and placental barriers. However, when radiolabeled simvastatin was administered to rats,
`simvastatin-derived radioactivity crossed the blood-brain barrier.
`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. Peak plasma
`concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours postdose. While the
`recommended therapeutic dose range is 5 to 80 mg/day, there was no substantial deviation from linearity
`of AUC of inhibitors in the general circulation with an increase in dose to as high as 120 mg. Relative to
`the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered
`immediately before an American Heart Association recommended low-fat meal.
`In a study including 16 elderly patients between 70 and 78 years of age who received ZOCOR
`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. Clinical study experience in the elderly
`(n=1522), suggests that there were no overall differences in safety between elderly and younger patients
`(see PRECAUTIONS, Geriatric Use).
`Kinetic studies with another reductase inhibitor, having a similar principal route of elimination, 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).
`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
`
`2
`
`

`
`ZOCOR® (simvastatin)
`
`7825441
`
`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 (see PRECAUTIONS, Drug Interactions). Grapefruit juice
`contains one or more components that inhibit CYP3A4 and can increase the plasma concentrations of
`drugs metabolized by CYP3A4. In one study**, 10 subjects consumed 200 mL of double-strength
`grapefruit juice (one can of frozen concentrate diluted with one rather than 3 cans of water) three times
`daily for 2 days and an additional 200 mL double-strength grapefruit juice together with and 30 and 90
`minutes following a single dose of 60 mg simvastatin on the third day. This regimen of grapefruit juice
`resulted in mean increases in the concentration (as 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 first** study, both before (for active inhibitors) and after (for total inhibitors) base hydrolysis] of
`1.13-fold and 1.18-fold, respectively, and of simvastatin and 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.
`Clinical Studies
`Coronary Heart Disease
`In 4S, the effect of therapy with ZOCOR on total mortality was assessed in 4,444 patients with CHD
`and baseline total cholesterol 212-309 mg/dL (5.5-8.0 mmol/L). In this multicenter, randomized, double-
`blind, placebo-controlled study, patients were treated with standard care, including diet, and either
`ZOCOR 20-40 mg/day (n=2,221) or placebo (n=2,223) for a median duration of 5.4 years. After six weeks
`of treatment with ZOCOR the median (25th and 75th percentile) changes in LDL-C, TG, and HDL-C were
`-39% (-46, -31%), -19% (-31, 0%), and 6% (-3, 17%). Over the course of the study, treatment with
`ZOCOR led to mean reductions in total-C, LDL-C and TG of 25%, 35%, and 10%, respectively, and a
`mean increase in HDL-C of 8%. ZOCOR significantly reduced the risk of mortality (Figure 1) by 30%,
`(p=0.0003, 182 deaths in the ZOCOR group vs 256 deaths in the placebo group). The risk of CHD
`mortality was significantly reduced by 42%, (p=0.00001, 111 vs 189 deaths). There was no statistically
`significant difference between groups in non-cardiovascular mortality. ZOCOR also significantly decreased
`the risk of having major coronary events (CHD mortality plus hospital-verified and silent non-fatal
`myocardial infarction [MI]) (Figure 2) by 34%, (p<0.00001, 431 vs 622 patients with one or more events).
`The risk of having a hospital-verified non-fatal MI was reduced by 37%. ZOCOR significantly reduced the
`risk for undergoing myocardial revascularization procedures (coronary artery bypass grafting or
`percutaneous transluminal coronary angioplasty) by 37%, (p<0.00001, 252 vs 383 patients). Furthermore,
`ZOCOR significantly reduced the risk of fatal plus non-fatal cerebrovascular events (combined stroke and
`transient ischemic attacks) by 28% (p=0.033, 75 vs 102 patients). ZOCOR reduced the risk of major
`coronary events to a similar extent across the range of baseline total and LDL cholesterol levels. Because
`there were only 53 female deaths, the effect of ZOCOR on mortality in women could not be adequately
`assessed. However, ZOCOR significantly lessened the risk of having major coronary events by 34% (60
`vs 91 women with one or more event). The randomization was stratified by angina alone (21% of each
`treatment group) or a previous MI. Because there were only 57 deaths among the patients with angina
`alone at baseline, the effect of ZOCOR on mortality in this subgroup could not be adequately assessed.
`However, trends in reduced coronary mortality, major coronary events and revascularization procedures
`were consistent between this group and the total study cohort. Additionally, in this study, 1,021 of the
`patients were 65 and older. Cholesterol reduction with simvastatin resulted in similar decreases in relative
`risk for total mortality, CHD mortality, and major coronary events in these elderly patients, compared with
`younger patients.
`
`
`** Lilja JJ, Kivisto KT, Neuvonen PJ. Clin Pharmacol Ther 1998;64(5):477-83.
`3
`
`

`
`ZOCOR® (simvastatin)
`
`7825441
`
`Figure 1
`
`Figure 2
`
`Simvastatin
`Placebo
`
`Log-rank p<0.00001
`
`1.00
`
`0.95
`
`0.90
`
`0.85
`
`0.80
`
`0.75
`
`0.70
`
`0.00
`
`Proportion without major CHD event
`
`Simvastatin
`Placebo
`
`Log-rank p=0.0003
`
`1.00
`
`0.95
`
`0.90
`
`0.85
`
`0.80
`
`0.75
`
`0.70
`
`0.00
`
`Proportion alive
`
`0
`
`1
`
`5
`
`6
`
`
`
`0
`
`1
`
`4
`3
`2
`Years since randomization
`
`5
`
`6
`
`4
`3
`2
`
`Years since randomization
`Angiographic Studies
`In the Multicenter Anti-Atheroma Study, the effect of therapy with simvastatin on atherosclerosis was
`assessed by quantitative coronary angiography in hypercholesterolemic men and women with coronary
`heart disease. In this randomized, double-blind, controlled study, patients with a mean baseline total-C
`value of 245 mg/dL (6.4 mmol/L) and a mean baseline LDL-C value of 170 mg/dL (4.4 mmol/L) were
`treated with conventional measures and with simvastatin 20 mg/day or placebo. Angiograms were
`evaluated at baseline, two and four years. A total of 347 patients had a baseline angiogram and at least
`one follow-up angiogram. The co-primary endpoints of the study were mean change per-patient in
`minimum and mean lumen diameters, indicating focal and diffuse disease, respectively. Simvastatin
`significantly slowed the progression of lesions as measured in the final angiogram by both these
`parameters (mean changes in minimum lumen diameter: –0.04 mm with simvastatin vs –0.12 mm with
`placebo; mean changes in mean lumen diameter: –0.03 mm with simvastatin vs –0.08 mm with placebo),
`as well as by change from baseline in percent diameter stenosis (0.9% simvastatin vs 3.6% placebo).
`After four years, the groups also differed significantly in the proportions of patients categorized with
`disease progression (23% simvastatin vs 33% placebo) and disease regression (18% simvastatin vs 12%
`placebo). In addition, simvastatin significantly decreased the proportion of patients with new lesions (13%
`simvastatin vs 24% placebo) and with new total occlusions (5% vs 11%). The mean change per-patient in
`mean and minimum lumen diameters, calculated by comparing angiograms, in the subset of 274 patients
`who had matched angiographic projections at baseline, two and four years is presented below (Figures 3
`and 4).
`
`Figure 3
`
`Mean Lumen Diameter
`(Mean and Standard Error)
`
`Change from Baseline (mm)
`
`NS
`
`0.02
`
`0
`
`-0.02
`
`-0.04
`
`-0.06
`
`-0.08
`
`-0.1
`
`Simvastatin
`(N=144)
`
`p=0.015
`
`Placebo
`(n=130)
`
`0
`
`-0.02
`
`-0.04
`
`-0.06
`
`-0.08
`
`-0.1
`
`-0.12
`
`-0.14
`
`Figure 4
`
`Minimum Lumen Diameter
`(Mean and Standard Error)
`
`Change from Baseline (mm)
`
`NS
`
`Simvastatin
`(N=144)
`
`p=0.013
`
`Placebo
`(n=130)
`
`0
`
`2
`
`4
`
`-0.16
`
`0
`
`-0.12
`
`
`Years
`Primary Hypercholesterolemia (Fredrickson type lla and llb)
`ZOCOR has been shown to be highly effective in reducing total-C and LDL-C in heterozygous familial
`and non-familial forms of hypercholesterolemia and in mixed hyperlipidemia. A marked response was
`seen within 2 weeks, and the maximum therapeutic response occurred within 4-6 weeks. The response
`was maintained during chronic therapy. Furthermore, improving lipoprotein levels with ZOCOR improved
`4
`
`2
`
`Years
`
`4
`
`

`
`ZOCOR® (simvastatin)
`
`7825441
`
`survival in patients with CHD and hypercholesterolemia treated with 20-40 mg/day for a median of 5.4
`years.
`In a multicenter, double-blind, placebo-controlled, dose-response study in patients with familial or non-
`familial hypercholesterolemia, ZOCOR given as a single dose in the evening (the recommended dosing)
`was similarly effective as when given on a twice-daily basis. ZOCOR consistently and significantly
`decreased total-C, LDL-C, total-C/HDL-C ratio, and LDL-C/HDL-C ratio. ZOCOR also decreased TG and
`increased HDL-C.
`The results of studies depicting the mean response to simvastatin in patients with primary
`hypercholesterolemia and combined (mixed) hyperlipidemia are presented in Table 1.
`TABLE 1
`Mean Response in Patients with Primary Hypercholesterolemia and Combined (mixed) Hyperlipidemia
`(Mean Percent Change from Baseline After 6 to 24 Weeks)
`
`TREATMENT
`
`N
`
`TOTAL-C
`
`LDL-C
`
`HDL-C
`
`TG*
`
`-12
`
`-15
`
`-2
`
`-19
`
`-18
`
`-24
`
`-4
`
`-28
`
`10
`
`12
`
`0 8
`
`9 8
`
`3 1
`
`3
`
`-26
`
`-30
`
`-1
`
`-38
`
`-41
`
`-47
`
`2
`
`-29
`
`Lower Dose Comparative Study
`(Mean % Change at Week 6)
`
`ZOCOR 5 mg q.p.m.
`
`ZOCOR 10 mg q.p.m.
`
`Scandinavian Simvastatin Survival Study
`(Mean % Change at Week 6)
`Placebo
`
`ZOCOR 20 mg q.p.m.
`
`Upper Dose Comparative Study
`(Mean % Change Averaged at
`Weeks 18 and 24)
`
`ZOCOR 40 mg q.p.m.
`
`ZOCOR 80 mg q.p.m.
`
`Multi-Center Combined Hyperlipidemia Study
`(Mean % Change at Week 6)
`
`Placebo
`
`ZOCOR 40 mg q.p.m.
`
`109
`
`110
`
`2223
`
`2221
`
`433
`
`664
`
`125
`
`123
`
`-19
`
`-23
`
`-1
`
`-28
`
`-31
`
`-36
`
`1
`
`-25
`
`124
`
`-31
`
`-36
`
`16
`
`-33
`
`ZOCOR 80 mg q.p.m.
`*median percent change
`In the Upper Dose Comparative Study, the mean reduction in LDL-C was 47% at the 80-mg dose. Of
`the 664 patients randomized to 80 mg, 475 patients with plasma TG ≤ 200 mg/dL had a median reduction
`in TG of 21%, while in 189 patients with TG > 200 mg/dL, the median reduction in TG was 36%. In these
`studies, patients with TG > 350 mg/dL were excluded.
`In the Multi-Center Combined Hyperlipidemia Study, a randomized, 3-period crossover study, 130
`patients with combined hyperlipidemia (LDL-C>130 mg/dL and TG: 300-700 mg/dL) were treated with
`placebo, ZOCOR 40, and 80 mg/day for 6 weeks. In a dose-dependent manner ZOCOR 40 and
`80 mg/day, respectively, decreased mean LDL-C by 29 and 36% (placebo: +2%) and median TG levels by
`28 and 33% (placebo: 4%), and increased mean HDL-C by 13 and 16% (placebo: 3%) and apolipoprotein
`A-I by 8 and 11% (placebo: 4%).
`Hypertriglyceridemia (Fredrickson type lV)
`The results of a subgroup analysis in 74 patients with type lV hyperlipidemia from a 130-patient
`double-blind, placebo-controlled, 3-period crossover study are presented in Table 2. The median baseline
`values (mg/dL) for the patients in this study were: total-C = 254, LDL-C = 135, HDL-C = 36, TG = 404,
`VLDL-C = 83, and non-HDL-C = 215.
`
`5
`
`

`
`ZOCOR® (simvastatin)
`
`7825441
`
`TABLE 2
`Six-week, Lipid-lowering Effects of Simvastatin in Type lV Hyperlipidemia
`Median Percent Change (25th and 75th percentile) from Baseline
`
`TREATMENT
`
`Placebo
`
`N
`
`74
`
`Total-C
`
`+2
`(-7,+7)
`
`LDL-C
`
`+1
`(-8, +14)
`
`ZOCOR 40 mg/day
`
`74
`
`-25
`(-34, -19)
`
`-28
`(-40, -17)
`
`ZOCOR 80 mg/day
`
`74
`
`-32
`(-38,-24)
`
`-37
`(-46,-26)
`
`HDL-C
`
`+3
`(-3, +10)
`
`+11
`(+5, +23)
`
`+15
`(+5, +23)
`
`TG
`
`VLDL-C
`
`Non-HDL-C
`
`-9
`(-25, +13)
`
`-7
`(-25, +11)
`
`+1
`(-9, +8)
`
`-29
`(-43, -16)
`
`-34
`(-45, -18)
`
`-37
`(-54, -23)
`
`-41
`(-57, -28)
`
`-32
`(-42, -23)
`
`-38
`(-49, -32)
`
`Dysbetalipoproteinemia (Fredrickson type lll)
`The results of a subgroup analysis in 7 patients with type lll hyperlipidemia (dysbetalipoproteinemia)
`(apo E2/2) (VLDL-C/TG>0.25) from a 130-patient double-blind, placebo-controlled, 3-period crossover
`study are presented in Table 3. In this study the median baseline values (mg/dL) were: total-C = 324,
`LDL-C = 121, HDL-C = 31, TG = 411, VLDL-C = 170, and non-HDL-C = 291.
`TABLE 3
`Six-week, Lipid-lowering Effects of Simvastatin in Type lll Hyperlipidemia
`Median Percent Change (min,max) from Baseline
`
`TREATMENT
`
`Placebo
`
`ZOCOR 40 mg/day
`
`ZOCOR 80 mg/day
`
`N
`
`7
`
`7
`
`7
`
`Total-C
`
`-8
`(-24,+34)
`
`-50
`(-66,-39)
`
`-52
`(-55,-41)
`
`LDL-C + IDL
`
`HDL-C
`
`TG
`
`VLDL-C+IDL
`
`Non-HDL-C
`
`-8
`(-27,+23)
`
`-50
`(-60,-31)
`
`-51
`(-57,-28)
`
`-2
`(-21,+16)
`
`+7
`(-8,+23)
`
`+7
`(-5,+29)
`
`+4
`(-22,+90)
`
`-41
`(-74,-16)
`
`-38
`(-58,+2)
`
`-4
`(-28,+78)
`
`-58
`(-90,-37)
`
`-60
`(-72,-39)
`
`-8
`(-26,-39)
`
`-57
`(-72,-44)
`
`-59
`(-61,-46)
`
`Homozygous Familial Hypercholesterolemia
`familial
`In a controlled clinical study, 12 patients 15-39 years of age with homozygous
`hypercholesterolemia received simvastatin 40 mg/day in a single dose or in 3 divided doses, or 80 mg/day
`in 3 divided doses. Eleven of the 12 patients had reductions in LDL-C. In those patients with reductions,
`the mean LDL-C changes for the 40- and 80-mg doses were 14% (range 8% to 23%, median 12%) and
`30% (range 14% to 46%, median 29%), respectively. One patient had an increase of 15% in LDL-C.
`Another patient with absent LDL-C receptor function had an LDL-C reduction of 41% with the 80-mg dose.
`Endocrine Function
`In clinical studies, simvastatin did not impair adrenal reserve or significantly reduce basal plasma
`cortisol concentration. Small reductions from baseline in basal plasma testosterone in men were observed
`in clinical studies with simvastatin, an effect also observed with other inhibitors of HMG-CoA reductase
`and the bile acid sequestrant cholestyramine. There was no effect on plasma gonadotropin levels. In a
`placebo-controlled 12-week study there was no significant effect of simvastatin 80 mg on the plasma
`testosterone response to human chorionic gonadotropin (hCG). In another 24-week study, simvastatin
`20-40 mg had no detectable effect on spermatogenesis. In 4S, in which 4,444 patients were randomized
`to simvastatin 20-40 mg/day or placebo for a median duration of 5.4 years, the incidence of male sexual
`adverse events in the two treatment groups was not significantly different. Because of these factors, the
`small changes in plasma testosterone are unlikely to be clinically significant. The effects, if any, on the
`pituitary-gonadal axis in pre-menopausal women are unknown.
`
`INDICATIONS AND USAGE
`Therapy with lipid-altering agents should be considered in those individuals at increased risk for
`atherosclerosis-related clinical events as a function of cholesterol level, the presence of CHD, or other risk
`factors. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol
`when the response to diet and other nonpharmacological measures alone has been inadequate (see
`National Cholesterol Education Program [NCEP] Treatment Guidelines, below).
`6
`
`

`
`ZOCOR® (simvastatin)
`
`7825441
`
`Coronary Heart Disease
`In patients with coronary heart disease and hypercholesterolemia, ZOCOR is indicated to:
`•
`Reduce the risk of total mortality by reducing coronary death;
`•
`Reduce the risk of non-fatal myocardial infarction;
`•
`Reduce the risk for undergoing myocardial revascularization procedures;
`•
`Reduce the risk of stroke or transient ischemic attack.
`(For a discussion of efficacy results in the elderly and other pre-defined subgroups, see CLINICAL
`PHARMACOLOGY, Clinical Studies.)
`Hyperlipidemia
`• ZOCOR is indicated to reduce elevated total-C, LDL-C, Apo B, and TG, and to increase HDL-C in
`patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed
`dyslipidemia (Fredrickson types IIa and IIb***).
`• ZOCOR is indicated for the treatment of patients with hypertriglyceridemia (Fredrickson type lV
`hyperlipidemia).
`• ZOCOR is indicated for the treatment of patients with primary dysbetalipoproteinemia (Fredrickson
`type lll hyperlipidemia).
`• ZOCOR is also indicated to reduce 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.
`General Recommendations
`Prior to initiating therapy with simvastatin, secondary causes for hypercholesterolemia (e.g., poorly
`controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver
`disease, other drug therapy, alcoholism) should be excluded, and a lipid profile performed to measure
`total-C, HDL-C, and TG. For patients with TG less than 400 mg/dL (< 4.5 mmol/L), LDL-C can be
`estimated using the following equation:
`LDL-C = total-C – [(0.20 x TG) + HDL-C]
`For TG levels > 400 mg/dL (> 4.5 mmol/L), this equation is less accurate and LDL-C concentrations
`should be determined by ultracentrifugation. In many hypertriglyceridemic patients, LDL-C may be low or
`normal despite elevated total-C. In such cases, ZOCOR is not indicated.
`Lipid determinations should be performed at intervals of no less than four weeks and dosage adjusted
`according to the patient's response to therapy.
`The NCEP Treatment Guidelines are summarized in Table 4:
`
`
`
`
`*** Classification of Hyperlipoproteinemias
`
`Lipoproteins
`elevated
`Type
`chylomicrons
`I (rare)
`LDL
`IIa
`LDL, VLDL
`IIb
`IDL
`III (rare)
`VLDL
`IV
`chylomicrons, VLDL
`V (rare)
`C = cholesterol, TG = triglycerides,
`LDL = low-density lipoprotein,
`VLDL = very-low-density lipoprotein,
`IDL = intermediate-density lipoprotein.
`
`Lipid
`Elevations
`major
`minor
`↑→C
`TG
`C
`—
`C
`TG
`C/TG
`—
`↑→C
`TG
`↑→C
`TG
`
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`ZOCOR® (simvastatin)
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`7825441
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` LDL Level at Which to
`Consider Drug Therapy
` (mg/dL)
` ≥130
` (100-129: drug optional)††
`
`
`
` 10-year risk 10-20%: ≥130
`10-year risk <10%: ≥ 160
`
`
`
` TABLE 4
` NCEP Treatment Guidelines:
`LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes
` and Drug Therapy in Different Risk Categories
`
` LDL Level at Which to
` LDL Goal
` Initiate Therapeutic Lifestyle Changes
` (mg/dL)
` (mg/dL)
` <100
` ≥100
`
`
`
` ≥130
`
` ≥190
` (160-189: LDL-lowering drug
`optional)
`
`CHD, coronary heart disease
`Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C level of <100 mg/dL cannot be achieved by therapeutic
`lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL-C, e.g., nicotinic acid or fibrate. Clinical judgment also may
`call for deferring drug therapy in this subcategory.
`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.
`
`
`
`≥160
`
`
`
` <130
`
`
`
` <160
`
`
`Risk Category
`
` CHD† or CHD risk equivalents
` (10-year risk >20%)
`
` 2+ Risk factors
` (10 year risk ≤20%)
`
` 0-1 Risk factor†††
`
`
`†
`††
`
`†††
`
`After the LDL-C goal has been achieved, if the TG is still ≥200 mg/dL, non-HDL-C (total-C minus
`HDL-C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C
`goals for each risk category.
`At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug
`therapy at discharge if the LDL-C is ≥ 130 mg/dL (see NCEP Treatment Guidelines, above).
`Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels be used to
`initiate and assess treatment response. Only if LDL-C levels are not available, should the total-C be used
`to monitor therapy.
`ZOCOR is indicated to reduce elevated LDL-C and TG levels in patients with Type IIb hyperlipidemia
`(where hypercholesterolemia is the major abnormality). However, it has not been studied in conditions
`where the major abnormality is elevation of chylomicrons (i.e., hyperlipidemia Fredrickson types I
`and V).***
`
`CONTRAINDICATIONS
`Hypersensitivity to any component of this medication.
`Active liver disease or unexplained persistent elevations of serum transaminases (see WARNINGS).
`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 ZOCOR to decrease the synthesis of
`cholesterol and possibly other products of
`the cholesterol biosynthesis pathway, ZOCOR
`is
`contraindicated during pregnancy and in nursing mothers. ZOCOR 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, ZOCOR should be discontinued immediately and the patient should be
`apprised of the potential hazard to the fetus (see PRECAUTIONS, Pregnancy).
`
`WARNINGS
`Skeletal Muscle
`Simvastatin and other inhibitors of HMG-CoA reductase occasionally cause myopathy, which is
`manifested as muscle pain or weakness associated with grossly elevated creatine kinase (CK) (> 10X the
`upper limit of normal [ULN]). Rhabdomyolysis, with or without acute renal failure secondary to
`myoglobinuria, has been reported rarely. In 4S, there was one case of myopathy among 1,399 patients
`taking simvastatin 20 mg and no cases among 822 patients taking 40 mg/day for a median duration of 5.4
`years. In two 6-month controlled clinical studies, there was one case of myopathy among 436 patients
`taking 40 mg and 5 cases among 669 patients taking 80 mg. The risk of myopathy is increased by
`
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`
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`
`concomitant therapy with certain drugs, some of which were excluded by the designs of these studies (see
`below).
`Myopathy caused by drug interactions.
`The incidence and severity of myopathy are increased by concomitant administration of HMG-CoA
`reductase inhibitors with drugs that can cause myopathy when given alone, such as gemfibrozil and other
`fibrates, and lipid-lowering doses (≥ 1 g/day) of niacin (nicotinic acid).
`In addition, the risk of myopathy may be increased by high levels of HMG-CoA reductase inhibitory
`activity in plasma. Simvastatin is metabolized by the cytochrome P450 isoform 3A4 (CYP3A4). Potent
`inhibitors of this metabolic pathway can raise the plasma levels of HMG-CoA reductase inhibitory activity
`and may increase the risk of myopathy. These include cyclosporine; the azole antifungals, itraconazole
`and ketoconazole; the macrolide antibiotics, erythromycin and clarithromycin; HIV protease inhibitors; the
`antidepressant nefazodone; and large quantities of grapefruit juice (> 1 quart daily) (see below; CLINICAL
`PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug
`Interactions; and DOSAGE AND
`ADMINISTRATION, Dosage in Patients taking Cyclosporine).
`The risk of myopathy appears to be increased by concomitant administration of verapamil (see
`PRECAUTIONS, Drug Interactions). In an analysis of clinical trials involving 25,248 patients treated with
`simvastatin 20 to 80 mg, the incidence of myopathy was higher in patients receiving verapamil and
`simvastatin (4/635; 0.63%) than in patients taking simvastatin without a calcium channel blocker
`(13/21,224; 0.061%).
`Reducing the risk of myopathy.
`1. General measures. Patients starting therapy with simvastatin should be advised of the risk
`of myopathy, and told to report promptly unexplained muscle pain, tenderness or weakness. A CK
`level above 10X ULN in a patient with unexplained muscle symptoms indicates myopathy. Simvastatin
`therapy should be discontinued if myopathy is diagnosed or suspected. In most cases, when
`patients were promptly discontinued from treatment, muscle symptoms and CK increases resolved.
`Of the patients with rhabdomyolysis, many had complicated medical histories. Some had preexisting
`renal insufficiency, usually as a consequence of long-standing diabetes. In such patients, dose escalation
`requires caution. Also, as there are no known adverse consequences of brief interruption of therapy,
`treatment with simvastatin should be stopped a few days before elective major surgery and when any
`major acute medical or surgical condition supervenes.
`2. Measures to reduce the risk of myopathy caused by drug interactions (see above and
`PRECAUTI