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MEVACOR (Lovastatin) is a cholesterol lowering agent isolated from a strain of Aspergillus terreus. After oral ingestion, lovastatin, which is an inactive lactone, is hydrolyzed to the corresponding Beta-hydroxacid form. This is a principal metabolite and an inhibitor of 3-hydroxy-3- menthylglutaryl-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.

Lovastatin is [1S-[1alpha(R*), 3 alpha, 7Beta, 8Beta (2S*, 4S*), 8 aB]]-1, 2, 3, 7, 8, 8a-hexahydro-3, 7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl]-1-naphthalenyl 2-menthylbutanotate. The emp irical formula of lovastatin is C24H36O5 and its molecular weight is 404.55. Its structural formula is:

Lovastatin is a white, nonhygroscopic crystalline powder that is insoluble in water and sparingly soluble in ethanol, methanol, and acetonitrile. Tablets MEVACOR are supplied as 10 mg, 20 mg and 40 mg tablets for oral administration. In addition to the active ingredient lovastatin, each tablet contains the following inactive ingredients: cellulose, lactose, magnesium stearate, and starch. Butylated hydroxanisole (BHA) is added as a preservative. Tablets MEVACOR 10 mg also contain red ferric oxide and yellow ferric oxide. Tablets MEVACOR 20 mg also contain FD&C Blue 2. Tablets MEVACOR 40 mg also contain D&C Yellow 10 and FD&C Blue 2.

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The involvement of low-density lipoprotein (LDL) cholesterol in atherogenesis has been well- documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological studies have established that (high density lipoprotein) cholesterol are both risk factors for coronary heart disease. The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), coordinated by the National Institutes of Health (NIH) studied men aged 35-59 with total cholesterol levels 265mg/dL (6.8 mmol/L) or greater and triglyceride levels not more than 300 mg/dL (3.4 mmol/L). This seven-year, double-blind, placebo-controlled study demonstrated that lowering LDL cholesterol with diet and cholestyamine decreased the combined rate of coronary heart disease death plus non-fatal myocardial infarction.

MEVACOR has been shown to reduce both normal and elevated LDL cholesterol concentrations. LDL is formed from VDL and is catabolized predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of MEVACOR may involve both reduction of VLDL cholesterol concentration, and induction of the LDL receptor; leading to reduced production and/or increased catabolism of LDL cholesterol. Apolipoprotein B also falls substantially during treatment with MEVACOR. Since each LDL particle contains one molecule of apolipoprotein B, and since little apolipoprotein B is found in other lipoproteins, this strongly suggests that MEVACOR does not merely cause cholesterol to be lost from LDL, but also reduces the concentration of circulating LDL particles. In addition, MEVACOR can produce increases of variable magnitude in HDL cholesterol, and modestly reduces VLDL cholesterol and plasma triglycerides (see Tables I-IV under Clinical Studies). The effects of MEVACOR or Lp(a) fibrinogen, and certain other independant biochemical risk markers for coronary heart disease are unknown.

MEVACOR is a specific inhibitor of HMG-CoA to mevalonate. The conversation of HMG-CoA to mevalonate is an early step in the biosynthetic pathway for cholesterol.

Lovastatin is a lactone which 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 lovastatin.

Following an oral dose of 14C-labeled lovastatin in man, 10% of the dose was excreted in urine and 83% in feces. The latter represents absorbed drug equivalents excreted in bile, as well as any unabsorbed drug. Plasma concentrations of total radio activity (lovastatin plus 14C- metabolites) peaked at 2 hours and declined rapidly to about 10% of peak by 24 hours postdose. Absorption of lovastatin, estimated relative to an intravenous reference dose, in each of four animal species tested, averaged about 30% of an oral dose. In animal studies, after oral dosing, lovastatin had high selectivity for the liver, where it achieved substantially higher concentrations than in nontarget tissues. Lovastatin 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 hepatic extraction of lavastatin, the availability of drug to the general circulation is low and variable. In a single dose study in four hypercholesterolemic patients, it was estimated that less than 5% of an oral dose of lovastatin reaches the general circulation as active inhibitors. Following administration of lovastatin tablets the coefficient of varation, based on between-subject variability, was approximately 40% for the area under the curve (AUC) of total inhibitory activity in the general circulation.

Both lovastatin and its B-hydroxyacid metabolite are highly bound (95%) to human plasma proteins. Animal studies demonstrated that lovastatin crosses the blood-brain and placental barriers.

The major active metabolites present in human plasma are the B-hydroxyacid of lovastatin, its 6- hydroxy derivative, and two additional metabolites. Peak plasma concentrations of both active and total inhibitors were attained within 2 to 4 hours of dose administration. While the recommended therapeutic dose range is 10 to 80 mg/day, linearity of inhibitory activity in the general circulation was established by a single dose study employing lovastatin tablet-dosages from 60 to as high as 120 mg. With a once-a-day dosing regimen, plasma concentrations of total inhibitors over a dosing interval achieved a steady state between the second and third days of therapy and were about 1.5 times those following a single dose. When lovastatin was given under fasting condition, plasma concentrations of total inhibitors were on average about two- thirds those found when lovastatin was administered immediately after a standard test meal.

In a study of patients with severe insufficiency (creatinine clearance 10-30 mL/min) , the plasma concentrations of total inhibitors after a single dose of lovastatin were approximately two-fold higher than those in healthy volunteers.

Clinical Studies
MEVACOR has been shown to be highly effective in reducing total LDL cholesterol in the heterozygous familial and non-familial forms of primary 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 continuation of therapy. Single daily doses given in the evening were more effective than the same dose given in the morning, perhaps because cholesterol is synthesized mainly at night. In multicenter, double-blind studies in patients with familial or non-familial hypercholesterolemia, MEVACOR administered in doses ranging from 10 mg q.p.m. to 40 mg b.i.d. was compared to placebo. MEVACOR consistently and significantly decreased total plasma cholesterol (TOTAL- C), LDL cholesterol (LDL-C), total cholesterol/HDL cholesterol (TOTAL-C/HDL) ratio and LDL cholesterol/HDL-C) ratio. In addition, MEVACOR produced increases of variable magnitude in HDL cholesterol (HDL-C), and modestly decreased VLDL cholesterol (VLDL-C) and plasma triglycerides (TRIG). (see Tables I through IV for dose response results).

The results of a study in patients with primary hypercholesterolemia are presented in Table I.

MEVACOR vs. Placebo
(Mean Percent Change from Baseline After 6 Weeks)

                                                 LDL-C/  TOTAL-C/
DOSAGE        N    TOTAL-C   LDL-C     HDL-C     HDL-C    HDL-C     TRIG   

Placebo 33 -2 -1 -1 0 +1 +9 MEVACOR 10 mg q.p.m. 33 -16 -21 +5 -24 -19 -10 20 mg q.p.m 33 -19 -27 +6 -30 -23 +9 10 mg b.i.d 32 -19 -28 -8 -33 -25 -7 40 mg q.p.m 33 -22 -31 +5 -33 -25 -8 20 mg b.i.d 36 -24 -32 +2 -32 -24 -6

MEVACOR was compared to cholestyramine in a randomized open parallel study and to probucol in a double-blind parallel study. Both studies were performed with patients with hypercholesterolemia who were at high risk of myocardial infarction. Summary results of these two comparative studies are presented in Tables II & III.

MEVACOR vs Cholestyramine
(Percent Change from Baseline After 12 Weeks)

                                             LDL-C/  TOTAL-C/
                  (mean)  (mean)   (mean)    (mean)   (mean) (median) (mean)

MEVACOR 20mg b.i.d. 85 -27 -32 +9 -36 -31 -34 -21 40mg b.i.d. 88 -34 -42 +8 -44 -37 -31 -27 Cholestyramine 12g b.i.d. 88 -17 -23 +8 -27 -21 +2 +11

MEVACOR vs. Probucol
(Percent Change from Baseline After 14 Weeks)

                                           LDL-C/  TOTAL-C/
                 (mean)  (mean)  (mean)   (mean)   (mean)  (median)  (mean)

MEVACOR 40mg q.p.m. 47 -25 -32 +9 -38 -31 -37 -18 80mg q.p.m. 49 -30 -37 +11 -42 -36 -27 -17 40mg b.i.d. 47 -33 -40 +12 -45 -39 -40 -25 Probucol 500mg b.i.d. 97 -10 -8 -23 +26 +23 -13 +1

MEVACOR was studied in controlled trials in hypercholesterolemic patients with well-controlled non-insulin dependent diabetes mellitus with normal renal function. The effect of MEVACOR on lipids and lipoproteins and the safety profile of MEVACOR were similar to that demonstrated in studies in nondiabetics. MEVACOR had no clinically important effect on glycemic control or on the dose requirement of oral hypoglycemic agents.

Expanded Clinical Evaluation of Lovastatin (EXCEL) Study

MEVACOR was compared to placebo in 8,245 patients with hypercholesterolemia (total cholesterol 240-300 mg/dL [6.2 mmol/L - 7.6 mmol/L] LDL cholesterol > 160 mg/dL [4.1 mmol/L]) in the randomized, double-blind, parallel, 48-week EXCEL study. All changes in the lipid measurements (Table IV) in MEVACOR treated patients were dose-related and significantly different from placebo (p < or = 0.001). These results were sustained throughout the study.

MEVACOR vs Placebo
(Percent change from baseline - Average Values Between Weeks 12 and 48)

                                              LDL-C/  TOTAL/C
DOSAGE     N**  TOTAL-C   LDL-C     HDL-C     HDL-C    HDL-C    TRIG
                (mean)   (mean)    (mean)    (mean)   (mean)  (median)

Placebo 1663 +0.7 +0.4 +2.0 +0.2 +0.6 +4 MEVACOR 20mg qpm 1642 -17 -24 +6.6 -27 -21 -10 40mg qpm 1645 -22 -30 +7.2 -34 -26 -14 20mg bid 1646 -24 -34 +8.6 -38 -29 -16 40mg bid 1649 -29 -40 +9.5 -44 -34 -19 **Patients enrolled

in the Canadian Coronary Atherosclerosis Intervention Trial (CCAIT), the effect of therapy with lovastatin on coronary atherosclerosis was assessed by coronary angiograpy in hyperlipidemic patients. In the randomized, double-blind, controlled clinical trial, patients were treated with conventional measures (usually diet and 325 mg of aspirin every other day) and either lovastatin 20-80 mg daily or placebo Angiograms were evaluated at baseline and at two years by computerized quantitative coronary angiography (QCA). Lovastatin significantly slowed the progression of lesions as measured by the mean change per-patient in minimum lumen diameter (the primary endpoint) and percent diameter stenosis, and decreased the proportions of patients categorized with disease progression (33% vs. 50%) and with new lesions (16% vs. 32%).

In a similarly designed trial, the Monitored Atherosclerosis Regression Study (MARS), patients were treated with diet and either lovastatin 80 mg daily or placebo. No statistically significant difference between lovastatin and placebo was seen for the primary endpoint (mean change per patient in percentage diameter stenosis of all lesions), or for most secondary QCA endpoints. Visual assessment by -- ographers who formed a consensus opinion of overall angiographic change (Global Change Score) was also a secondary endpoint. By this end-point, significant slowing of disease was seen, with regression in 23% of patients treated with lovastatin compared to 11% of placebo patients.

In the Familial Atherosclerosis Treatment Study (FATS), either lovastatin or niacin in combination with a bile acid sequestrant for 2.5 years in hyperlipidemic subjects significantly reduced the frequency of progression and increased the frequency of regression of coronary atherosclerotic lesions by QCA compared to diet and, in some cases, low dose resin.

The effect of lovastatin on the progression of atherosclerosis in the coronary arteries has been corroborated by similar findings in another vasculature. In the Asymptomatic Carotid Artery Progression Study (ACAPS), the effect of therapy, with lovastatin on carotid atherosclerosis was assessed by B-mode ultrasonography in hyperlipidemic patients with early carotid lesion and without known coronary heart disease at baseline. In this double-blind, controlled clinical trial, 919 patients were randomized in a 2 x 2 factorial design to placebo, lovastatin 10-40 mg daily and/or warfarin. Ultrasonograms of the carotid walls were used to determine the change per patient from baseline to three years in mean maximum intimal-medial thickness (IMT) of 12 measured segments. There was a significant regresssion of carotid lesions in patients receiving lovastain alone compared to those receiving placevo alone (p=0.001). The predictive value of changes in IMT for stroke has not yet been established in the lovastatin group there was a significant reduction in the number of patients with major cardiovascular events relative to the placebo group (5 vs.14) and a significant reduction in all-cause mortality (1 vs. 8).

There was a high prevalence of baseline lenticular opacities in the patient population included in the early clinical trials with lovastatin. During these trials the appearance of new opacities was noted in both the lovastatin and placebo groups. There was no clinically significant change in visual acuity in the patients who had new opacities reported nor was any patient, including those with opacities noted at baseline, discontinued from therapy because of a decrease in visual acuity.

A three-year, double-blind, placebo-controlled study in hypercholesterolemic patients to assess the effect of lovastatin on the human lens demonstrated that there was no clinically or statistically significantly differences between the lovastatin and placebo groups in the incidence, type or progression of lenticular opacities. There are no controlled clinical data assessing the lens available for treatment beyond three years.

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Therapy with lipid-altering agents should be a component of multiple risk factor intervention in those individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. MEVACOR is indicated as an adjunct to diet for the reduction of elevated total and LDL cholesterol levels in patients with primary hypercholesterolemia (Types IIa and IIb***), when the response to diet restricted in saturated fat and cholesterol and to other nonpharmacological measures alone has been inadequate.

MEVACOR is also indicated to slow the progression of coronary atherosclerosis in patients with coronary heart diseases as part of a treatment strategy to lower total and LDL cholesterol to target levels. Most subjects in the angiographic studies were middle-aged men; therefore, it is not clear to what extent these data can be extrapolated to women and the elderly (see CLINICAL PHARMACOLOG, Clinical Studies).

Prior to initiating therapy with lovastatin, 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 triglycerides (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 cholesterol - [0.2 x (triglycerides) + 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 hypertriglyceridemic patients, LDL-C may be low whiormal despite elevated TOTAL-C. In such cases MEVACOR is not indicated.

The National Cholesterol Education Program (NCEP) Tratment Guidelines are summarized below:

LDL-Cholesterol mg/dL (mmol/L)
Definite Two or More Atherosclerotic Other Risk Initiation Disease* Factors** Level Goal
NO NO > or = 190 < 160 (> or = 4.9) (< 4.1) NO YES > 1 60 < 130 (> 4.1) (< 3.4) YES YES or NO > or = 130 < 100 (> or = 3.4) (< 2.6)
*Coronary heart disease or peripheral vascular-disease (including symptomatic carotid artery disease).
**Other risk factors for coronary heart disease (CHD) include: age (males: > or = 45 years; females: > or = 55 years or premature menopause without estrogen replacement therapy);family history of premature CHD: current cigarette smoking; hypertension; confirmed HDL-C < 35mg/dL (< 0.91 mmo/L); and diabetes mellitus. Subtract one risk factor if HDL-C > or = 60 mg/dL (> or = 1.6 mmol/L).

Since the goal of treatment is 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.

Although MEVACOR may be useful to reduce elevated LDL cholesterol levels in patients with combined hpyercholesterolemia and hypertriglyceridemia where hypercholesterolemia is the major abnormality (Type IIb hyperlipoproteinemia), it has not been studied in conditions where the major abnormality is elevation of chylomicrons, VLDL or IDL (i.e., hyperlipoproteinemia types I,III,IV,or V).***

***Classification of Hyperlipoproteinemias

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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 longterm 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 inhibtors of HMG-CoA reductase such as MEVACOR to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway, MEVACOR may cause fetal harm when administered to a pregnant woman. Therefore, lovastatin is contraindicated during pregnancy. Lovastatin 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, lovastatin should be discontinued and the patient should be apprised of the potential hazard to the fetus.

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Liver Dysfunction
Marked persistent increases (to more than 3 times the upper limit of normal) in serum transaminases occurred in 1.9% of adult patients who received lovastatin for at least one year in early clinical trials (see ADVERSE REACTIONS). When the drug was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. The increase usually appeared 3 to 12 months after the start of therapy with lovastatin, and were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity. In the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical Studies), the incidence of marked persistent increases in serum transaminases over 48 weeks was 0.1% for placebo, 0.1% at 20 mg/day, 0.9% at 40 mg/day, and 1.5% at 80 mg/day in patients on lovastatin. However, in post-marketing experience with MEVACOR, symptomatic liver disease has been reported rarely at all dosages (see ADVERSE REACTIONS).

It is recommended that liver function tests be performed before the initiation of treatment, at 6 and 12 weeks after initiation of therapy or elevation in dose, and periodically there after.(e.g, semiannually). 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 three times the upper limit of normal or greater persist, withdrawal of therapy with MEVACOR 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 disease or unexplained transaminase elevations are contraindication to the use of lovastatin.

As with other lipid-lowering agents, moderate (less than three times the upper limit of normal) elevations of serum transaminases have been reported following therapy with MEVACOR (see ADVERSE REACTIONS). These changes appeared soon after initiation of therapy with MEVACOR, were often transient, were not accompanied by any symptoms and interruption of treatment was not required.

Skeletal Muscle
Rhabdomyolysis has been associated with lovastatin therapy alone, when combined with immunosuppressive therapy including cyclosporine in cardia transplant patients, and when combined in non-transplant patients with either gemfibrozil or lipid-lowering doses (> or = 1g/day) of nicotinic acid. Some of the affected patients had pre-existing renal insufficiency, usually as a consequence of long-standing diabetes. Acute renal failure from rhabdomyolysis has been seen more commonly with the lovastatin-gemfibrozil combination, and has been reported in transplant patients receiving lovastatin plus cyclosporine.

Rhabdomyolysis with renal failure has been reported in a renal transplant patient receiving cyclosporine and lovastatin shortly after a dose increase in the systemic antifungal agent itraconazole. Another transplant patient on cyclosporine and a different HMG-CoA reductase inhibitor experienced muscle weakness accompanied by marked evelation of creatine phosphokinase following the initiation of systemic itraconazole therapy. The HMG-CoA reductase inhibitors and the azole derivative antifungal agents inhibit cholesterolµ(µ‹synthesis at different points in the biosynthetic pathway. In patients receiving clclosporine, lovastatin should be temporarily discontinued if systemic azole derivative antifungal therapy is required; patients not taking cyclosporine should be carefully monitored if systemic azole derivative antifungal therapy is required.

Rhabdomyolysis with or without renal impairment has been reported in seriously ill patients receiving erythromycin concomitantly with lovastatin. Therefore, patients receiving concomitant lovastatin and erythromycin should be carefully monitored.

Fulminant rhabdomyolysis has been seen as early as three weeks after initiation of combined therapy with gemfibrozil and lovastatin, but may be seen after several months. For these reasons, it is felt that, in most subjects who have had an unsatisfactory lipid response to either drug alone, the possible benefits of combined therapy with lovastatin and gemfibrozil do not outweigh the risks of severe myopathy, rhabdomyolysis, and acute renal failure. While it is not known whether this interaction occurs with fibrates other than gemfibrozil, myopathy and rhabdomyolysis have occasionally been associated with the use of other fibrates alone, including clofibrate. Therefore, the combined use of lovastatin with other fibrates should generally be avoided.

Physicians contemplating combined therapy with lovastatin and lipid-lowering doses of nicotinic acid or with immunosuppressive drugs should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Periodic CPK determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy. The monitoring of lovastatin drug and metabolite levels may be considered in transplant patients who are treated with immunosuppressives and lovastatin.

Lovastatin therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolys•®Ô=including: severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures.

Myalgia has been associated with lovastatin therapy. Transient, mildly elevated creatine phosphokinase levels are commonly seen in lovastatin treated patients. However, in early clinical trials, approximately 0.5% of patients developed a myopathy, i.e myalgia or muscle weakness associated with markedly elevated CPK levels. In the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical Studies), five (0.1%) patients taking lovastatin alone (one at 40 mg q.p.m., and four at 40 mg b.i.d) developed myopathy (muscle symptoms and CPK levels >10 times the upper limit of normal). Myopathy should be considered in any patient with diffuse myalgia, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Lovastatin therapy should be discontinued if markedly elevated CPK levels occur or myopoathy is diagnosed or suspected.

Most of the patients who have developed myopathy (including rhabdomyolysis) were taking lovastatin concomitantly with immunosuppressive drugs, gemfibrozil or lipid-lowering doses of nicotinic acid. In initial clinical trials, about 30 percent of patients on concomitant immunosuppressive therapy including cyclosporine developed myopathy. Most of these patients were receiving lovastatin at doses of 40 to 80 mg/day. In reports from 7 subsequent studies, 148 cyclosporine-treated patients (105 cardiac and 43 renal) received concurrent lovastatin doses of 10 to 60 mg/day (the majority receiving 20 mg/day) for mean periods of 3 to 15 months. There was one case of rhabdomyolysis (0.6%) and one case of significant CPK elevation. In earlier studies of patients taking lovastatin in combination with gemfibrozil or niacin the incidences of myopathy were approximately 5% and 2% respectively.

In six patients with cardiac transplants taking immunosuppressive therapy including cyclosporine concomitantly with lovastatin 20 mg/day, the average plasma level of active metabolites derived from lovastatin was elevated to approximately four times the expected levels. Because of an apparent relationship between increased plasma levels of active metabolites derived from lovasatin and myopathy, the daily dosage in patients taking immunosuppressants should not exceed 20 mg/day (see DOSAGE AND ADMINISTRATION). Even at this dosage, the benefits and risks of using lovastatin in patients taking immunosuppressants should be carefully considered.

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Before instituting therapy with MEVACOR, and attempt should be made to control hypercholesterolemia with appropriate diet, exercise, weight reduction in obese patients, and to treat other underlying medical problems(See indications and usage). Lovastatin may elevate creatine phosphokinase 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 lovastatin.

Homozygous Familial Hypercholesterolemia
MEVACOR is less effective in patients with the rare homozygous familial hypercholesterolemia, possibly because these patients have no functional LDL receptors. MEVACOR appears to be more likely to raise serum transaminases (see ADVERSE REACTIONS) in these homozygous patients.

Information for Patients
Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

Drug Interactions
Immunosuppressive Drugs, Itraconazole, Gemfibrozil, Niacin (Nicotinic Acid), Erythromycin: See WARNINGS, Skeletal Muscle.

Coumarin Anticoagulants: In a small clinical trial in which lovastatin was administered to warfarin treated patients, no effect on prothrombin time was detected. However, another HMG- CoA reductase inhibitor has been found to produce a less than two seconds increase in prothrombin time in healthy volunteers receiving low doses of warfarin. Also, bleeding and or increased prothrombin time have been reported in a few patients taking coumarin anticoagulants concomitantly with lovastatin. It is recommended that in patients taking anticogulants, prothrombin time be determined before starting lovastatin and frequently enough during early therapy to insure 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 lovastatin is changed, the same procedure should be repeated. Lovastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.

Antipyrine: Because lovastatin had no effect on the pharmacokinetics of antipyrine or its metabolites, interactions of other drugs metabolized via the same cytochrome isozymes are not expected.

Propranolol: In normal volunteers, there was no clinically significant pharmacokinetic or pharmacodynamic interaction with concomitant administration of single doses of lovastatin and propranolol.

Digoxin: In patients with hypercholesterolemia, concomitant administration of lovastatin and digoxin resulted in no effect on digoxin plasma concentrations.

Oral Hypoglycemic Agents: In pharmacokinetic studies of MEVACOR in hypercholesterolemic non-insulin dependent diabetic patients, there was no drug interaction with glipizide or with chlorpropamide (see CLINICAL PHARMACOLOGY , Clinical Studies).

Other Concomitant Therapy: Although specific interaction studies were not performed, in clinical studies, lovastatin was used concomitantly with beta blockers, calcium channel blockers, diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs) without evidence of clinically significant adverse interactions.

Endocrine Function
HMG_CoA reductase inhibitors interfere with cholesterol synthesis and as such might theroretically blunt adrenal and or gonadal steroid production. Results of clinical trials with drugs in this class have been inconsistent with regard to drug effects on basal and reserve steroid levels. However, clinical studies have shown that lovastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve, and does not reduce basal plasma testosterone concentration. Another HMG-CoA reductase inhibitor has been shown to reduce the plasma testosterone response to HCG. In the same study, the mean testosterone response to HCG was slightly but not significantly reduced after treatment with lovastatin 40 mg daily for 16 weeks in 21 men. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of male patients. The effects, if any on the pituitary-gonadal axis in pre-menopausal women are unknown. Patients treated with lovastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be exercised if an HMG_CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients also receiving other drugs.(eg, ketoconazole, spironolactone, cimetidine) that may decrease the levels or activity of endogenous steroid hormones.

CNS Toxicity
Lovastatin 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 drug level in humans taking the highest recommended dose (as measured by total enzyme ingibitory activity). Vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis were also seen in dogs treated for 14 weeks at 180 mg/kg/day, a dose which resulted in a mean plasma drug level (Cmax) similar to that seen with the 60 mg/kg/day dose.

CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltratio nof perivascular spaces, perivascular fibrin deposits and necrosis of small vessels, were seen in dogs treated with lovastatin at a dose of 180mg/kg/day, a dose which produced plasma drug levels(Cmax) which were about 30 times higher-than the mean values in humans taking 80 mg/day.

Similar optic nerve and CNS vascular lesions have been observed with other drugs of this class.

Cataracts were seen in dogs treated for 11 and 28 weeks at 180mg/kg/day and 1 year at 60 mg/kg/day.

Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 21 month carcinogenic study in mice, there was a statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in both male and females at 500 mg/kg/day. This dose produced a total plasma drug exposure 3 to 4 times that of humans given the highest recommended dose of lovastatin (drug exposure was measured as total HMG-CoA reductase inhibitory activity in extracted plasma). Tumor increases were not seen at 20 and 100 mg/kg/day, doses that produced drug exposures of 0.3 to 2 times that of humans at the 80 mg/day dose. A statistically significant increase in pulmonary adenomas was seen in female mice at approximately 4 times the human drug exposure. (Although mice were given 300 times the human dose [HD] on a mg/kg body weight basis, plasma levels of total inhibitory activity were only 4 times higher in mice than in humans given 80 mg of MEVACOR.)

There was an increase in incidence of papilloma in the nonglandular mucosa of the stomach of mice beginning at exposures of 1 to 2 times that of humans. The glandular mucosa was not affected. The human stomach contains only glandular mucosa.

In a 24-month carcinogenicity study in rats, there was a positive dose response relationship for hepatocellular carcinogenicity in males at drug exposures between 2-7 times that of human exposure at 80 mg/day (doses in rats were 5, 30 and 180 mg/kg/day).

An increased incidence of thyroid neoplasms in rats appears to be a response that has been seen with other HMG-CoA reductase inhibitors.

A chemically similar drug in this class was administered to mice for 72 weeks at 25, 100 and 400mg/kg body weight, which resulted in mean serum drug levels approximately 3, 15, and 33 times higher than the mean human serum drug concentration (as total inhibitory activity) after a 40 mg oral dose. Liver carcinomas were significantly increased in high dose females and mid- and high dose males, with maximum incidence of 90 percent 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 mutagenicity was observed in a microbial mutagen test using mutant strains of Salmonella typhimurium with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat or mouse hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow.

Drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation were seen in dogs starting at 20 mg/kg/day. Similar findings were seen with another drug in this class. No drug-related effects on fertility were found in studies with lovastatin in rats. However, in studies with a similar drug in this class, there was decreased fertility in male rats treated for 34 weeks at 25 mg/kg/day body weight, although this effect was not observed in a subsequent fertility study when this same dose was administered for 11 weeks (the entire cycle of spermatogenesis, including epididymal maturation). In rats treated with this same reductase inhibitor at 180 mg/kg/day, seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. No microscopic changes were observed in the testes from rats of either study. The clinical significance of these findings is unclear.

Pregnancy Category X

Safety in pregnant women has not been established. Lovastatin has been shown to produce skeletal malformations at plasma levels 40 times the human exposure (for mouse fetus) and 80 times the human eposure (for rat fetus) based on mg/m2 surface area (doses were 800 mg/kg/day). No drug-induced changes were seen in either species at multiples of 8 times (rat) or 4 times (mouse) based on surface area. No evidence of malformations was noted in rabbits at exposures up to 3 times the human exposure (dose of 15 mg/kg/day, highest tolerated dose). Rare reports of congenital anomalies have been received following intrauterine exposure to HMG_CoA reductase inhibitors. There has been one report of severe congenital bony deformity, tracheo-esophageal fistula, and anal atresia (VATER association) in a baby born to a woman who took lovastatin with dextroamphetamine sulfate during the first timester of pregnancy. MEVACOR should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the woman becomes pregnant while taking MEVACOR, it should be discontinued and the patient advised again as to the potential hazards to the fetus.

Nursing Mothers
It is not known whether lovastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human breast milk and because of the potential for serious adverse reactions in nursing infants, women taking MEVACOR should not nurse their infants (see CONTRAINDICATIONS).

Pediatric Use
Safety and effectiveness in children and adolescents have not been established. Because children and adolescents are not likely to benefit from cholesterol lowering for at least a decade and because experience with this drug is limited (no studies in subjects below the age of 20 years), treatment of children with lovastatin is not recommended at this time.

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MEVACOR is generally well tolerated; adverse reactions usually have been mild and transient. Less than 1% of patients were discontinued from controlled clinical studies of up to 14 weeks due to adverse experiences attributable to MEVACOR. About 3% of patients were discontinued from extensions of these studies due to adverse experiences attributable to MEVACOR; about half of these patients were discontinued due to increases in serum transaminases. The median duration of therapy in these extensions was 5.2 years.

In the EXCEL study ( see CLINICAL PHARMACOLOGY, Clinical Studies), 4.6% of the patients treated up to 48 weeks were discontinued due to clinical or laboratory adverse experiences which were rated by the investigator as possibly, probably or definitely related to therapy with MEVACOR. The value for the placebo group was 2.5%.

Clinical Averse Experiences
Adverse experiences reported in patients treated with MEVACOR in controlled clinical studies are shown in the table below.

                     MEVACOR     Placebo    Cholestyramine   Probucol
                     (N=613)      (N=82)        (N=88)        (N=97)
                        %           %             %             %

Gastrointestinal Constipation 4.9 -- 34.1 2.1 Diarrhea 5.5 4.9 8.0 10.3 Dyspepsia 3.9 -- 13.6 3.1 Flatus 6.4 2.4 21.6 2.1 Abdominal pain/cramps 5.7 2.4 5.7 5.2 Heartburn 1.6 -- 8.0 -- Nausea 4.7 3.7 9.1 6.2 Musculoskeletal Muscle cramps 1.1 -- 1.1 -- Myalgia 2.4 1.2 -- -- Nervous System/Psychiatric Dizziness 2.0 1.2 -- 1.0 Headache 9.3 4.9 4.5 8.2 Skin Rash/pruritus 5.2 -- 4.5 -- Special Senses Blurred vision 1.5 -- 1.1 3.1 Dysgeusia 0.8 -- 1.1 --
Laboratory Tests
Marked persistent increases of serum transaminases have been noted (see WARNINGS).

About 11% of patients had elevations of creatine phosphokinase (CPK) levels of at least twice the normal value on one or more occasions. The corresponding values for the control agents were cholestyramine, 9 percent and probucol, 2 percent. This was attributable to the noncardiac fraction of CPK. Large increases in CPK have sometimes been reported (see WARNINGS, Skeletal Muscle).

Expanded Clinical Evaluation of Lovastatin (EXCEL) Study
Clinical Adverse Experiences

MEVACOR was compared to placebo in 8,245 patients with hypercholesterolemia (total cholesterol 240,300 mg/dL in the randomized, double-blind, parallel, 48-week EXCEL study. Clinical adverse experiences reported as possibly, probably or definitely drug-related in > or = to 1% in any treatment group are shown in the table below. For no event was the incidence on drug and placebo statistically different.

                Placebo    MEVACOR      MEVACOR      MEVACOR      MEVACOR
                         20mg q.p.m.  40mg q.p.m.  20mg b.i.d.  40mg b.i.d.
               (N=1663)   (N=1642)     (N=1645)     (N=1646)      (1649)
                   %          %            %            %            %

Body As a Whole Asthenia 1.4 1.7 1.4 1.5 1.2 Gastrointestinal Abdominal pain 1.6 2.0 2.0 2.2 2.5 Constipation 1.9 2.0 3.2 3.2 3.5 Diarrhea 2.3 2.6 2.4 2.2 2.6 Dyspepsia 1.9 1.3 1.3 1.0 1.6 Flatulence 4.2 3.7 4.3 3.9 4.5 Nausea 2.5 1.9 2.5 2.2 2.2 Musculoskeltal Muscle Cramps 0.5 0.6 0.8 1.1 1.1 Myalgia 1.7 2.6 1.8 2.2 3.0 Nervous System/ Psychiatric Dizziness 0.7 0.7 1.2 0.5 0.5 Headache 2.7 2.6 2.8 2.1 3.2 Skin Rash 0.7 0.8 1.0 1.2 1.3 Special Senses Blurred vision 0.8 1.1 0.9 0.9 1.2

Other clinical adverse experiences reported as possibly, probably or definitely drug-related in 0.5 to 1.0 percent of patients in any drug-treated group are listed below. In all these cases the incidence on drug and placebo was not statistically different. Body as a Whole: chest pain; Gastrointestinal: acid regurgitation, dry mouth, vomiting; Musculoskeletal: leg pain, shoulder pain, arthralgia; Nervous System/Psychiatric: insomnia, paresthesia; skin: alopecia, pruritus; Special Senses: eye irritation.

Concomitant Therapy
In controlled clinical studies in which lovastatin was administered concomitantly with cholestyramine, no adverse reactions peculiar to this concomitant treatment were observed. The adverse reactions that occurred were limited to those reported previously with lovastatin or cholestyramine. Other lipid-lowering agents were not administered concomitantly with lovastatin during controlled clinical studies. Preliminary data suggests that the addition of either probucol or gemfibrozil to therapy with lovastatin is not associated with greater reduction in LDL cholesterol than that achieved with lovastatin alone. In uncontrolled clinical studies, most of the patients who have developed myopathy were receiving concomitant therapy with immunosuppressive drugs, gemfibrozil or niacin (nicotinic acid) (see WARNINGS Skeletal Muscle).

The following effects have been reported with drugs in this class. Not all the effects listed below have necessarily been associated with lovastatin therapy.
Skeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias.
Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, dizziness, vertigo, memory loss, paresthesia, peripheral neuropathy, peripheral nerve palsy, psychic distrubances, anxiety, insomnia, depression.
Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malai se, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.
Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver; and rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma; anorexia, vomiting.
Skin: alopecia, pruritus. A variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails) have been reported.
Reproductive: gynecomastia, loss of libido, erectile dysfunction.
Eye: progression of cataracts (lens opacities), ophthalmoplegia.
Laboratory Abnormalities: elevated transaminases, alkaline phosphatase, gamma-glutamyl transpeptidase, and bilirubin; thyroid function abnormalities.

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After oral administration of MEVACOR to mice the median lethal dose observed was >15 g/m2.

Five healthy human volunteers have received up to 200 mg of lovastatin as a single dose without clinically significant adverse experiences. A few cases of accidental overdosage have been reported; no patients had any specific symptoms, and all patients recovered without sequelae. The maximum dose taken was 5-6g.

Until further experience is obtained, no specific treatment of overdosage with MEVACOR can be recommended.

The dialyzability of lovastatin and its metabolites in man is not known at present.

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The patient should be placed on a standard cholesterol-lowering diet before receiving MEVACOR and should continue on this diet during treatment with MEVACOR (see NCEP Treatment Guidelines for details on dietary therapy). MEVACOR should be given with meals.

The usual recommended starting dose is 20 mg once a day given with the evening meal. The recommended dosing range is 10-80 mg/day in single or two divided doses; the maximum recommended dose is 80 mg/day. Doses should be individualized according to the recommended goal of therapy (see NCEP Guidelines) and the patient’s response (see Tables I to IV under CLINICAL PHARMACOLOGY, Clinical Studies for some response results). Patients requiring reductions in LDL cholesterol of 20% or more to achieve their goal (see INDICATIONS AND USAGE) should be started on 20 mg/day of MEVACOR. A starting dose of 10 mg may be considered for patients requiring smaller reductions. Adjustments should be made at intervals of 4 weeks or more.

In patients taking immunosupressive drugs concomitantly with lovastatin (see WARNINGS, Skeletal Muscle), therapy should begin with 10 mg of MEVACOR and should not exceed 20 mg/day.

Cholesterol levels should be monitored periodically and consideration should be given to reducing the dosage of MEVACOR if cholesterol levels fall significantly below the targeted range.

Concomitant Therapy
Preliminary evidence suggests that the cholesterol lowering effects of lovastatin and the bile acid sequestrant, cholestyramine, are additive.

Dosage in Patients with Renal Insufficiency
In patients with severe renal insufficiency (creatinine clearance <30 mL/min), dosage increases above 20 mg/day should be carefully considered and, if deemed necessary, implemented cautiously (see CLINICAL PHARMACOLOGY AND WARNINGS, Skeletal Muscle).

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No. 3560- Tablets MEVACOR 10 MG are peach, octagonal tablets, coded MSD 730 on one side and MEVACOR on the other, they are supplied as follows:

NDC 0006-0730-61 unit of use bottles of 60.

No.3561- Tablets MEVACOR 20 mg are light blue, octagonal tablets, coded MSD 731 on one side and MEVACOR on the other. They are supplied as follows:

NDC 0006-0731-37 unit of use bottles of 30
NDC 0006-0731-61 unit of use bottles of 60
(6505-01-267-2497,20 mg 60's)
NDC 0006-0731-94 unit of use bottles of 90
NDC 0006-0731-28 unit dose package of 100
(6505-01-267-7925,20mg 100's)
NDC 0006-0731-78 unit of use bottles of 100
NDC 0006-0731-98 bottles of 180
NDC 0006-0731-82 bottles of 1000
(6505-01-359-1865, 20 mg,1000’s)
NDC 0006-0731-87 bottles of 10,000
(6505-01-379-7905, 20mg 10,000's).

No. 3562-Tablets MEVACOR 40 mg are green, octagonal tablets, coded MSD 732 on one side and MEVACOR on the other. They are supplied as follows:

NDC 0006-0732-61 unit of use bottles of 60
(6505-01-310-0615, 40 mg 60's)
NDC 0006-0732-94 unit of use bottles of 90
NDC 0006-0731-82 bottles of 1,000
NDC 0006-0372-87 bottles of 10,000
(6505-01-379-7903, 40mg 10,000's).

Store between 5-30oC (41-86oF). Tablets MEVACOR must be protected from light and stored in a well-closed, light-resistant container.

Dist. by:

West Point, PA 19486, USA
Issued February 1996
Printed in USA

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