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Merck's Investigational Extended-Release Niacin/Laropiprant (CORDAPTIVE(TM)) Coadministered with Simvastatin Had Significant Additive Effects on LDL-C, HDL-C and Triglycerides in Phase III Study

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Nov 5, 2007 - Extended-release niacin/laropiprant (CORDAPTIVE(TM)) coadministered with simvastatin had significant additive effects on reducing LDL-cholesterol (LDL-C), increasing HDL-cholesterol (HDL-C) and reducing triglyceride levels in a Phase III study with patients with primary hypercholesterolemia or mixed dyslipidemia. The results were presented today by Merck & Co., Inc. at the American Heart Association 2007 Scientific Sessions in Orlando, Fla.

In the study, 2 g (two 1-gram tablets) of CORDAPTIVE coadministered with simvastatin (pooled across 20 mg or 40 mg doses) reduced LDL-C by 48 percent, increased HDL-C by 28 percent, and reduced triglyceride levels by 33 percent following 12 weeks of treatment. The primary study endpoint was LDL-C reduction; secondary endpoints included increased HDL-C, triglyceride reduction and effects on other lipoproteins. A 1 g tablet of CORDAPTIVE contains 1 g of Merck-developed extended-release niacin and 20 mg of laropiprant - a novel flushing pathway inhibitor that is designed to reduce the flushing associated with niacin. All of the comparative lipid efficacy results were measured as mean percent change from baseline and were statistically significant, p < 0.001.

"The results in this study suggest that, if approved, CORDAPTIVE used with a statin could offer another approach to treat patients with dyslipidemia," said Christie M. Ballantyne, M.D., associate chief and professor of medicine, Baylor College of Medicine, and co-author of the study.

About the study

The double-blind, parallel, 12-week study with seven treatment arms in almost 1400 patients evaluated 1 g of CORDAPTIVE (1 g extended-release niacin/20 mg laropiprant) coadministered with simvastatin 10 mg to 40 mg in weeks one through four and 2 g of CORDAPTIVE (two 1-gram tablets each containing 1 g extended-release niacin/20 mg of laropiprant) coadministered with simvastatin 20 mg to 40 mg in weeks five through 12 (n = 590). Tolerability and the safety profile of CORDAPTIVE coadministered with simvastatin were also evaluated.

Reported lipid results in other treatment arms included a 17 percent decrease in LDL-C, 23 percent increase in HDL-C, and 22 percent decrease in triglycerides with CORDAPTIVE alone (n = 192); and a 37 percent reduction in LDL-C, six percent increase in HDL-C and 15 percent reduction in triglycerides with simvastatin alone (pooled) (n = 585).

About the tolerability of CORDAPTIVE

Reported side effects of interest included: liver enzyme elevations greater than or equal to 3x ULN in ALT and/or AST (0.3 percent with CORDAPTIVE coadministered with simvastatin, 0.5 percent with CORDAPTIVE alone, and 1.0 percent with simvastatin alone), and increased median fasting plasma glucose values (4.0 mg/dL with CORDAPTIVE plus simvastatin, 4.0 mg/dL with CORDAPTIVE alone, and 1.0 mg/dL with simvastatin alone). There were no cases of creatine kinase (CK) levels greater than or equal to 10x ULN in the group treated with CORDAPTIVE coadministered with simvastatin, which was not significantly different than that of the group treated with CORDAPTIVE or simvastatin alone (0.5 percent and 0.3 percent, respectively). All elevations were asymptomatic and resolved with discontinuation of treatment. There were no cases of myopathy, rhabdomyolysis or drug-related hepatitis.

Discontinuations due to flushing were 4.8 percent in the group treated with CORDAPTIVE coadministered with simvastatin, 8.7 percent with CORDAPTIVE alone and 0.3 percent with simvastatin alone.

Flushing pathway

Niacin-induced flushing is primarily caused by a prostaglandin, PGD(2), a chemical that causes vasodilation in the skin and flushing symptoms, acting through the DP(1) flushing pathway. Laropiprant selectively blocks the binding of PGD(2)to its receptor, DP(1). Research has shown blocking DP(1) reduces flushing associated with niacin.

"It has been shown that niacin-based therapies reduce the risk of cardiovascular events. But even though niacin has broad lipid effects, the flushing side effect has been a barrier to many patients reaching the maximum 2 g dose," said John Paolini, M.D., Ph.D., Clinical Research, Cardiovascular Disease, Merck Research Laboratories.


CORDAPTIVE is in development by Merck for the treatment of elevated LDL-C, low HDL-C and elevated triglycerides. Merck has previously announced that the New Drug Application for CORDAPTIVE has been accepted by the U.S. Food and Drug Administration (FDA), and regulatory action is anticipated in the second quarter of 2008. Merck is also on track to file a New Drug Application in 2008 for the Company's investigational compound MK-0524B.

About dyslipidemia

Dyslipidemia is the elevation of LDL-C and/or triglycerides or a low HDL-C level that contributes to the development of atherosclerosis, the number one cause of death among men and women and the primary reason for loss of quality of life in Western countries. Major modifiable risk factors for atherosclerotic disease include hypertension, diabetes, obesity, smoking and high levels of total cholesterol or LDL-C. Low levels of HDL-C also increase a person's chances of developing atherosclerosis. In fact, epidemiologic studies have shown that for every 1 mg/dL rise in HDL-C, the risk of developing cardiovascular disease decreases by two percent to three percent.

About cardiovascular risk factors

Cardiovascular disease (CVD) is a general term referring to diseases that affect the heart or blood vessels. Coronary heart disease (CHD), also known as coronary artery disease (CAD), is one of the most common forms of CVD and is the leading cause of death globally. Major risk factors for CVD include abnormal lipids, meaning not only high LDL-C ("bad" cholesterol) and triglyceride levels, but also low levels of HDL-C ("good" cholesterol). Researchers hypothesize that HDL takes part in the reverse transport of cholesterol from peripheral tissues in the body back to the liver for elimination. It is also theorized that HDL suppresses vascular inflammation associated with atherosclerosis and may potentially reduce the risk of injury to blood vessels through an anti-oxidative effect. Sixty-six percent of patients on current lipid lowering therapy have at least one lipid outside current recommendations.

Important considerations about simvastatin

Simvastatin, a cholesterol-modifying medicine from Merck, and marketed under the brand name ZOCOR(R), is used in addition to diet to modify cholesterol levels after diet and other non-drug measures have failed to achieve target levels.

Simvastatin should not be used by anyone allergic to any of its components, with liver disease, or by women who are pregnant, breast-feeding or likely to become pregnant. Muscle pain or weakness in people taking simvastatin should be reported to a doctor because these could be signs of a serious side effect. Doctors may perform blood tests before and periodically during treatment with simvastatin to check for liver problems. People taking 80 mg of simvastatin should receive an additional liver function test at three months. To help avoid serious side effects, discuss with your doctor medicine or food you should avoid while taking simvastatin. In most clinical trials, adverse reactions usually have been mild or transient. Most common side effects included headache (3.5 percent), abdominal pain (3.2 percent) and constipation (2.3 percent).

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit

Forward-looking statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2006, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.

Prescribing information for ZOCOR is attached.





ZOCOR(1) (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 B-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-(1a,3a,7B,8B(2S*,4S*),-8aB)). 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.


Epidemiological studies have demonstrated that elevated levels of total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), as well as decreased levels of high-density lipoprotein cholesterol (HDL-C) are associated with the development of atherosclerosis and increased cardiovascular risk. Lowering LDL-C decreases this risk. However, the independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.


Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding B-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic studies of the B-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. 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. Since simvastatin undergoes extensive first-pass extraction in the liver, the availability of the drug to the general circulation is low (<5%).

Both simvastatin and its B-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. Rat studies indicate that when radiolabeled simvastatin was administered, simvastatin-derived radioactivity crossed the blood-brain barrier.

The major active metabolites of simvastatin present in human plasma are the B-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 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 HMG-CoA reductase inhibitors. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4.

The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. 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).

Gemfibrozil: Coadministration of gemfibrozil (600 mg twice daily for 3 days) with simvastatin (40 mg daily) resulted in clinically significant increases in simvastatin acid AUC (185%) and Cmax (112%), possibly due to inhibition of simvastatin acid glucuronidation by gemfibrozil (see WARNINGS, Myopathy/Rhabdomyolysis, PRECAUTIONS, Drug Interactions, DOSAGE AND ADMINISTRATION).

Fenofibrate: Coadministration of fenofibrate (160 mg daily) with ZOCOR (80 mg daily) for 7 days had no effect on plasma AUC (and Cmax) of either total HMG-CoA reductase inhibitory activity or fenofibric acid; there was a modest reduction (approximately 35%) of simvastatin acid which was not considered clinically significant (see WARNINGS, Myopathy/Rhabdomyolysis, PRECAUTIONS, Drug Interactions).

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(2), 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 B-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(2) 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 B-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 in Adults

Reductions in Risk of CHD Mortality and Cardiovascular Events

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 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)) 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.

The Heart Protection Study (HPS) was a large, multi-center, placebo-controlled, double-blind study with a mean duration of 5 years conducted in 20,536 patients (10,269 on ZOCOR 40 mg and 10,267 on placebo). Patients were allocated to treatment using a covariate adaptive method(3) which took into account the distribution of 10 important baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients had a mean age of 64 years (range 40-80 years), were 97% Caucasian and were at high risk of developing a major coronary event because of existing coronary heart disease (65%), diabetes (Type 2, 26%; Type 1, 3%), history of stroke or other cerebrovascular disease (16%), peripheral vessel disease (33%), or hypertension in males 65 years of age and older (6%). At baseline, 3,421 patients (17%) had LDL-C levels below 100 mg/dL, of whom 953 (5%) had LDL-C levels below 80 mg/dL; 7,068 patients (34%) had levels between 100 and 130 mg/dL; and 10,047 patients (49%) had levels greater than 130 mg/dL.

The HPS results showed that ZOCOR 40 mg/day significantly reduced: total and CHD mortality; non-fatal myocardial infarctions, stroke, and revascularization procedures (coronary and non-coronary) (see Table 1). -0-

                               TABLE 1

              Summary of Heart Protection Study Results

Endpoint                    ZOCOR       Placebo      Risk     p-Value

                          (N=10,269)   (N=10,267)   Reduction

                            n (%)+       n (%)+        (%)

                                                    (95% CI)



Mortality                1,328 (12.9) 1,507 (14.7)  13 (6-19) p=0.0003

 CHD mortality              587 (5.7)    707 (6.9)  18 (8-26) p=0.0005



 Non-fatal MI               357 (3.5)    574 (5.6) 38 (30-46) p<0.0001

 Stroke                     444 (4.3)    585 (5.7) 25 (15-34) p<0.0001




 revascularization            513 (5)    725 (7.1) 30 (22-38)  p0.0001

 Peripheral and other


  revascularization         450 (4.4)    532 (5.2)  16 (5-26)  p=0.006

+ n = number of patients with indicated event

Two composite endpoints were defined in order to have sufficient events to assess relative risk reductions across a range of baseline characteristics (see Figure 1). A composite of major coronary events (MCE) was comprised of CHD mortality and non-fatal MI (analyzed by time-to-first event; 898 patients treated with ZOCOR had events and 1,212 patients on placebo had events). A composite of major vascular events (MVE) was comprised of MCE, stroke and revascularization procedures including coronary, peripheral and other non-coronary procedures (analyzed by time-to-first event; 2,033 patients treated with ZOCOR had events and 2,585 patients on placebo had events). Significant relative risk reductions were observed for both composite endpoints (27% for MCE and 24% for MVE, p<0.0001). Furthermore, treatment with ZOCOR produced significant relative risk reductions for all components of the composite endpoints. The risk reductions produced by ZOCOR in both MCE and MVE were evident and consistent regardless of cardiovascular disease related medical history at study entry (i.e., CHD alone; or peripheral vascular disease, cerebrovascular disease, diabetes or treated hypertension, with or without CHD), gender, age, creatinine levels up to the entry limit of 2.3 mg/dL, baseline levels of LDL-C, HDL-C, apolipoprotein B and A-1, baseline concomitant cardiovascular medications (i.e., aspirin, beta blockers, or calcium channel blockers), smoking status, alcohol intake, or obesity. Diabetics showed risk reductions for MCE and MVE due to ZOCOR treatment regardless of baseline HbA1c levels or obesity with the greatest effects seen for diabetics without CHD. -0-

                               Figure 1

The Effects of Treatment with ZOCOR on Major Vascular Events and Major

                        Coronary Events in HPS


N= number of patients in each subgroup. The inverted triangles are point estimates of the relative risk, with their 95% confidence intervals represented as a line. The area of a triangle is proportional to the number of patients with MVE or MCE in the subgroup relative to the number with MVE or MCE, respectively, in the entire study population. The vertical solid line represents a relative risk of one. The vertical dashed line represents the point estimate of relative risk in the entire study population.

Angiographic Studies

In the Multicenter Anti-Atheroma Study, the effect of simvastatin on atherosclerosis was assessed by quantitative coronary angiography in hypercholesterolemic patients with coronary heart disease. In this randomized, double-blind, controlled study, patients were treated with simvastatin 20 mg/day or placebo. Angiograms were evaluated at baseline, two and four years. The co-primary study endpoints 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 Year 4 angiogram by both parameters, as well as by change in percent diameter stenosis. In addition, simvastatin significantly decreased the proportion of patients with new lesions and with new total occlusions.

Modifications of Lipid Profiles

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. 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 (see Table 2). -0-

                               TABLE 2

   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+


 Lower Dose Comparative Study ++


(Mean % Change at Week 6)


 ZOCOR 5 mg q.p.m.                        109     -19   -26    10  -12

 ZOCOR 10 mg q.p.m.                       110     -23   -30    12  -15

 Scandinavian Simvastatin Survival Study



(Mean % Change at Week 6)


 Placebo                                 2223      -1    -1     0   -2

 ZOCOR 20 mg q.p.m.                      2221     -28   -38     8  -19


Upper Dose Comparative Study ||


(Mean % Change Averaged at


Weeks 18 and 24)


ZOCOR 40 mg q.p.m.                        433     -31   -41     9  -18

ZOCOR 80 mg q.p.m.                        664     -36   -47     8  -24

 Multi-Center Combined Hyperlipidemia

---------------------------------------- (Mean % Change at Week 6) ---------------------------------------- Placebo 125 1 2 3 -4 ZOCOR 40 mg q.p.m. 123 -25 -29 13 -28 ZOCOR 80 mg q.p.m. 124 -31 -36 16 -33 ---------------------------------------------------------------------- + median percent change ++ mean baseline LDL-C 244 mg/dL and median baseline TG 168 mg/dL ss. mean baseline LDL-C 188 mg/dL and median baseline TG 128 mg/dL || mean baseline LDL-C 226 mg/dL and median baseline TG 156 mg/dL mean baseline LDL-C 156 mg/dL and median baseline TG 391 mg/dL.

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 greater than 200 mg/dL, the median reduction in TG was 36%. In these studies, patients with TG greater than 350 mg/dL were excluded.

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 3. -0-

                               TABLE 3

     Six-week, Lipid-lowering Effects of Simvastatin in Type lV


   Median Percent Change (25th and 75th percentile) from Baseline+


             TREATMENT              N   Total-C     LDL-C      HDL-C


Placebo                                    +2         +1        +3

                                    74  (-7, +7)  (-8, +14)  (-3, +10)

ZOCOR 40 mg/day                           -25        -28        +11

                                    74 (-34, -19) (-40, -17) (+5, +23)

ZOCOR 80 mg/day                           -32        -37        +15

                                    74 (-38, -24) (-46, -26) (+5, +23)


              TREATMENT                   TG       VLDL-C   Non-HDL-C


Placebo                                   -9         -7         +1

                                      (-25, +13) (-25, +11)  (-9, +8)

ZOCOR 40 mg/day                          -29        -37        -32

                                      (-43, -16) (-54, -23) (-42, -23)

ZOCOR 80 mg/day                          -34        -41        -38

                                      (-45, -18) (-57, -28) (-49, -32)


+ 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.

Dysbetalipoproteinemia (Fredrickson type lll)

The results of a subgroup analysis in 7 patients with type lll hyperlipidemia (dysbetalipoproteinemia) (apo E2/2) (VLDL-C/TGgreater than0.25) from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 4. 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. -0-

                               TABLE 4

     Six-week, Lipid-lowering Effects of Simvastatin in Type lll


            Median Percent Change (min,max) from Baseline


TREATMENT                          N  Total-C   LDL-C + IDL   HDL-C


Placebo                                  -8         -8          -2

                                   7 (-24, +34) (-27, +23)  (-21, +16)

ZOCOR 40 mg/day                         -50         -50         +7

                                   7 (-66, -39) (-60, -31)  (-8, +23)

ZOCOR 80 mg/day                         -52         -51         +7

                                   7 (-55, -41) (-57, -28)  (-5, +29)


TREATMENT                                 TG     VLDL-C+IDL Non-HDL-C


Placebo                                   +4         -4         -8

                                      (-22, +90) (-28, +78) (-26, -39)

ZOCOR 40 mg/day                          -41        -58        -57

                                      (-74, -16) (-90, -37) (-72, -44)

ZOCOR 80 mg/day                          -38        -60        -59

                                      (-58, +2)  (-72, -39) (-61, -46)


Homozygous Familial Hypercholesterolemia

In a controlled clinical study, 12 patients 15-39 years of age with homozygous familial 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.

Clinical Studies in Adolescents

In a double-blind, placebo-controlled study, 175 patients (99 adolescent boys and 76 post-menarchal girls) 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (heFH) were randomized to simvastatin (n=106) or placebo (n=67) for 24 weeks (base study). Inclusion in the study required a baseline LDL-C level between 160 and 400 mg/dL and at least one parent with an LDL-C level greater than189 mg/dL. The dosage of simvastatin (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter. In a 24-week extension, 144 patients elected to continue therapy and received simvastatin 40 mg or placebo.

ZOCOR significantly decreased plasma levels of total-C, LDL-C, and Apo B (see Table 5). Results from the extension at 48 weeks were comparable to those observed in the base study. -0-

                               TABLE 5

  Lipid-lowering Effects of Simvastatin in Adolescent Patients with

              Heterozygous Familial Hypercholesterolemia

                 (Mean Percent Change from Baseline)

Dosage           Duration  N                 Total-C         LDL-C


                              % Change

Placebo         24 Weeks  67     from

                               Baseline       1.6            1.1

                               (95% CI)   (-2.2, 5.3)    (-3.4, 5.5)



                                 mg/dL       278.6          211.9

                                 (SD)        (51.8)         (49.0)


                              % Change

ZOCOR           24 Weeks  106    from

                               Baseline      -26.5          -36.8

                               (95% CI)  (-29.6, -23.3) (-40.5, -33.0)



                                 mg/dL       270.2          203.8

                                 (SD)        (44.0)         (41.5)


Dosage                            HDL-C         TG+          Apo B


Placebo                            3.6         -3.2          -0.5

                               (-0.7, 8.0) (-11.8, 5.4)  (-4.7, 3.6)

                                  46.9         90.0         186.3

                                 (11.9)       (50.7)        (38.1)


ZOCOR                              8.3         -7.9         -32.4

                               (4.6, 11.9) (-15.8, 0.0) (-35.9, -29.0)

                                  47.7         78.3         179.9

                                  (9.0)       (46.0)        (33.8)


+ median percent change

After 24 weeks of treatment, the mean achieved LDL-C value was 124.9 mg/dL (range: 64.0-289.0 mg/dL) in the ZOCOR 40 mg group compared to 207.8 mg/dL (range: 128.0-334.0 mg/dL) in the placebo group.

The safety and efficacy of doses above 40 mg daily have not been studied in children with heterozygous familial hypercholesterolemia. The long-term efficacy of simvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.


Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol (see National Cholesterol Education Program (NCEP) Treatment Guidelines, below).

In patients with CHD or at high risk of CHD, ZOCOR can be started simultaneously with diet.

Reductions in Risk of CHD Mortality and Cardiovascular Events

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, ZOCOR is indicated to:

-- Reduce the risk of total mortality by reducing CHD deaths.

-- Reduce the risk of non-fatal myocardial infarction and stroke.

-- Reduce the need for coronary and non-coronary revascularization procedures.

Patients with Hypercholesterolemia Requiring Modifications of Lipid Profiles

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(4)).

-- Treat patients with hypertriglyceridemia (Fredrickson type lV hyperlipidemia).

-- Treat patients with primary dysbetalipoproteinemia (Fredrickson type lll hyperlipidemia).

-- 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.

Adolescent Patients with Heterozygous Familial Hypercholesterolemia (HeFH)

ZOCOR is indicated as an adjunct to diet to reduce total-C, LDL-C, and Apo B levels in adolescent boys and girls who are at least one year post-menarche, 10-17 years of age, with heterozygous familial hypercholesterolemia, if after an adequate trial of diet therapy the following findings are present:

-- 1. LDL cholesterol remains (greater than=)190 mg/dL; or

-- 2. LDL cholesterol remains (greater than=)160 mg/dL and

-- There is a positive family history of premature cardiovascular disease (CVD) or

-- Two or more other CVD risk factors are present in the adolescent patient.

The minimum goal of treatment in pediatric and adolescent patients is to achieve a mean LDL-C <130 mg/dL. The optimal age at which to initiate lipid-lowering therapy to decrease the risk of symptomatic adulthood CAD has not been determined.

General Recommendations

Prior to initiating therapy with simvastatin, secondary causes for hypercholesterolemia (e.g., 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: -0-

               LDL-C = total-C - ((0.20 x TG) + HDL-C)

For TG levels greater than 400 mg/dL (greater than 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 6: -0-

                               TABLE 6

                      NCEP Treatment Guidelines:

     LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes

            and Drug Therapy in Different Risk Categories


                        LDL Goal    LDL Level at Which  LDL Level at

    Risk Category       (mg/dL)             to             Which to

                                        Initiate       Consider Drug

                                       Therapeutic         Therapy

                                     Lifestyle Changes     (mg/dL)



 CHD+ or CHD risk

     equivalents          100            (>=)100           (>=)130

                                                       (100-129: drug

(10-year risk >20%)                                      optional)++

                                                        10-year risk


  2+ Risk factors         130            (>=)130           (>=)130

   (10-year risk                                        10-year risk

      (<=)20%)                                           10%: (>=)160

 0-1 Risk factorss.       160            (>=)160           (>=)190

                                                       (160-189: LDL-

                                                        lowering drug



+ 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.

ss. 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.

After the LDL-C goal has been achieved, if the TG is still (greater than=)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.

The NCEP classification of cholesterol levels in pediatric patients with a familial history of either hypercholesterolemia or premature cardiovascular disease is summarized in Table 7. -0-

                               TABLE 7

   NCEP Classification of Cholesterol Levels in Pediatric Patients

       with a Familial History of Either HeFH or Premature CVD


   Category           Total-C (mg/dL)             LDL-C (mg/dL)


  Acceptable               <170                        <110

  Borderline              170-199                    110-129

     High                 (>=)200                    (>=)130


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).(4)


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).



Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.

As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related. In a clinical trial database in which 41,050 patients were treated with ZOCOR with 24,747 (approximately 60%) treated for at least 4 years, the incidence of myopathy was approximately 0.02%, 0.08% and 0.53% at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.

All patients starting therapy with simvastatin or whose dose of simvastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with simvastatin or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.

Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. Therapy with simvastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.

The risk of myopathy/rhabdomyolysis is increased by concomitant use of simvastatin with the following:

Potent inhibitors of CYP3A4: Simvastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of cytochrome P450 3A4 (CYP3A4). When simvastatin is used with a potent inhibitor of CYP3A4, elevated plasma levels of HMG-CoA reductase inhibitory activity can increase the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin.

The use of simvastatin concomitantly with the potent CYP3A4 inhibitors itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, or large quantities of grapefruit juice (greater than1 quart daily) should be avoided. Concomitant use of other medicines labeled as having a potent inhibitory effect on CYP3A4 should be avoided unless the benefits of combined therapy outweigh the increased risk. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin should be suspended during the course of treatment.

Gemfibrozil, particularly with higher doses of simvastatin: The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with gemfibrozil. The combined use of simvastatin with gemfibrozil should be avoided, unless the benefits are likely to outweigh the increased risks of this drug combination.

Other lipid-lowering drugs (other fibrates or (greater than=)1 g/day of niacin): Caution should be used when prescribing other fibrates or lipid-lowering doses ((greater than=)1 g/day) of niacin with simvastatin, as these agents can cause myopathy when given alone. The benefit of further alterations in lipid levels by the combined use of simvastatin with other fibrates or niacin should be carefully weighed against the potential risks of these combinations.

Cyclosporine or danazol, with higher doses of simvastatin: The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with cyclosporine or danazol. The benefits of the use of simvastatin in patients receiving cyclosporine or danazol should be carefully weighed against the risks of these combinations.

Amiodarone or verapamil, with higher doses of simvastatin: The dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with amiodarone or verapamil. The combined use of simvastatin at doses higher than 20 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy. In an ongoing clinical trial, myopathy has been reported in 6% of patients receiving simvastatin 80 mg and amiodarone. 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%).

Prescribing recommendations for interacting agents are summarized in Table 8 (see also CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions; DOSAGE AND ADMINISTRATION). -0-

                               TABLE 8

             Drug Interactions Associated with Increased

                   Risk of Myopathy/Rhabdomyolysis


Interacting Agents        Prescribing Recommendations


Itraconazole              Avoid simvastatin





HIV protease inhibitors



Gemfibrozil               Do not exceed 10 mg simvastatin daily




Amiodarone                Do not exceed 20 mg simvastatin daily



Grapefruit juice          Avoid large quantities of grapefruit juice

                           (>1 quart daily)


Liver Dysfunction

Persistent increases (to more than 3X the ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin in clinical studies. When drug treatment was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. The increases were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity.

In 4S (see CLINICAL PHARMACOLOGY, Clinical Studies), the number of patients with more than one transaminase elevation to greater than 3X ULN, over the course of the study, was not significantly different between the simvastatin and placebo groups (14 (0.7%) vs. 12 (0.6%)). Elevated transaminases resulted in the discontinuation of 8 patients from therapy in the simvastatin group (n=2,221) and 5 in the placebo group (n=2,223). Of the 1,986 simvastatin treated patients in 4S with normal liver function tests (LFTs) at baseline, only 8 (0.4%) developed consecutive LFT elevations to greater than 3X ULN and/or were discontinued due to transaminase elevations during the 5.4 years (median follow-up) of the study. Among these 8 patients, 5 initially developed these abnormalities within the first year. All of the patients in this study received a starting dose of 20 mg of simvastatin; 37% were titrated to 40 mg.

In 2 controlled clinical studies in 1,105 patients, the 12-month incidence of persistent hepatic transaminase elevation without regard to drug relationship was 0.9% and 2.1% at the 40- and 80-mg dose, respectively. No patients developed persistent liver function abnormalities following the initial 6 months of treatment at a given dose.

It is recommended that liver function tests be performed before the initiation of treatment, and thereafter when clinically indicated. Patients titrated to the 80-mg dose should receive an additional test prior to titration, 3 months after titration to the 80-mg dose, and periodically thereafter (e.g., semiannually) for the first year of treatment. Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality(ies) return to normal. Should an increase in AST or ALT of 3X ULN or greater persist, withdrawal of therapy with ZOCOR is recommended.

The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are contraindications to the use of simvastatin.

As with other lipid-lowering agents, moderate (less than 3X ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes appeared soon after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and did not require interruption of treatment.



Simvastatin may cause elevation of CK and transaminase levels (see WARNINGS and ADVERSE REACTIONS). This should be considered in the differential diagnosis of chest pain in a patient on therapy with simvastatin.

Information for Patients

Patients should be advised about substances they should not take concomitantly with simvastatin and be advised to report promptly unexplained muscle pain, tenderness, or weakness (see list below and WARNINGS, Myopathy/Rhabdomyolysis). Patients should also be advised to inform other physicians prescribing a new medication that they are taking ZOCOR.

Drug Interactions

CYP3A4 Interactions

Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Potent inhibitors of CYP3A4 (below) increase the risk of myopathy by reducing the elimination of simvastatin.

See WARNINGS, Myopathy/Rhabdomyolysis, and CLINICAL PHARMACOLOGY, Pharmacokinetics. -0-






HIV protease inhibitors


Large quantities of grapefruit juice (greater than1 quart daily)

Interactions with lipid-lowering drugs that can cause myopathy when given alone

See WARNINGS, Myopathy/Rhabdomyolysis.

The risk of myopathy is increased by gemfibrozil (see DOSAGE AND ADMINISTRATION) and to a lesser extent by other fibrates and niacin (nicotinic acid) ((greater than=)1 g/day).

Other drug interactions

Cyclosporine or Danazol: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol particularly with higher doses of simvastatin (see CLINICAL PHARMACOLOGY, Pharmacokinetics; WARNINGS, Myopathy/Rhabdomyolysis).

Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone or verapamil with higher doses of simvastatin (see WARNINGS, Myopathy/Rhabdomyolysis).

Propranolol: In healthy male volunteers there was a significant decrease in mean Cmax, but no change in AUC, for simvastatin total and active inhibitors with concomitant administration of single doses of ZOCOR and propranolol. The clinical relevance of this finding is unclear. The pharmacokinetics of the enantiomers of propranolol were not affected.

Digoxin: Concomitant administration of a single dose of digoxin in healthy male volunteers receiving simvastatin resulted in a slight elevation (less than 0.3 ng/mL) in digoxin concentrations in plasma (as measured by a radioimmunoassay) compared to concomitant administration of placebo and digoxin. Patients taking digoxin should be monitored appropriately when simvastatin is initiated.

Warfarin: In two clinical studies, one in normal volunteers and the other in hypercholesterolemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. With other reductase inhibitors, clinically evident bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly. In such patients, prothrombin time should be determined before starting simvastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of simvastatin is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.

CNS Toxicity

Optic nerve degeneration was seen in clinically normal dogs treated with simvastatin for 14 weeks at 180 mg/kg/day, a dose that produced mean plasma drug levels about 12 times higher than the mean plasma drug level in humans taking 80 mg/day.

A chemically similar drug in this class also produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean plasma drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose that resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose.

CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels were seen in dogs treated with simvastatin at a dose of 360 mg/kg/day, a dose that produced mean plasma drug levels that were about 14 times higher than the mean plasma drug levels in humans taking 80 mg/day. Similar CNS vascular lesions have been observed with several other drugs of this class.

There were cataracts in female rats after two years of treatment with 50 and 100 mg/kg/day (22 and 25 times the human AUC at 80 mg/day, respectively) and in dogs after three months at 90 mg/kg/day (19 times) and at two years at 50 mg/kg/day (5 times).

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of 25, 100, and 400 mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8 times higher than the mean human plasma drug level, respectively (as total inhibitory activity based on AUC) after an 80-mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males with a maximum incidence of 90% in males. The incidence of adenomas of the liver was significantly increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No evidence of a tumorigenic effect was observed at 25 mg/kg/day.

In a separate 92-week carcinogenicity study in mice at doses up to 25 mg/kg/day, no evidence of a tumorigeni

Posted: November 2007