LOVASTATIN- lovastatin_tablet

The involvement of low-density lipoprotein cholesterol (LDL-C) in atherogenesis has been well-documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological and clinical studies have established that high LDL-C and low high-density lipoprotein cholesterol (HDL-C) are both associated with coronary heart disease. However, the risk of developing coronary heart disease is continuous and graded over the range of cholesterol levels and many coronary events do occur in patients with total cholesterol (total-C) and LDL-C in the lower end of this range. Lovastatin has been shown to reduce elevated LDL-C concentrations. LDL is formed from very low-density lipoprotein (VLDL) and is catabolized predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of lovastatin may involve both reduction of VLDL-C concentration, and induction of the LDL receptor, leading to reduced production and / Lovastatin is a specific inhibitor of HMG-CoA reductase, the enzyme which catalyzes the conversion of HMG-CoA to mevalonate. The conversion of HMG-CoA to mevalonate is an early step in the biosynthetic pathway for cholesterol. Lovastatin is a lactone which is readily hydrolyzed in vivo Following an oral dose of 14 14 Both lovastatin and its beta-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 beta-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 / In a study of patients with severe renal insufficiency (creatinine clearance 10 to 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. In a study including 16 elderly patients between 70 to 78 years of age who received lovastatin 80 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18 to 30 years of age ( see PRECAUTIONS, Geriatric Use 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 lovastatin and lovastatin 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. Strong inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy (see WARNINGS, Myopathy/Rhabdomyolysis PRECAUTIONS, Drug Interactions Lovastatin is a substrate for cytochrome P450 isoform 3A4 (CYP3A4) (see PRECAUTIONS, Drug Interactions 1 1 TABLE I The Effect of Other Drugs on Lovastatin Exposure When Both Were Co-administered Number of Subjects Dosing of Coadministered Drug or Grapefruit Juice Dosing of Lovastatin AUC Ratio Results based on a chemical assay. ( with / without coadministered drug ) No Effect = 1. 00 Lovastatin Lovastatin acid Lovastatin acid refers to the beta-hydroxyacid of lovastatin. Gemfibrozil 11 600 mg BID for 3 days 40 mg 0. 80 Itraconazole The mean total AUC of lovastatin without itraconazole phase could not be determined accurately. Results could be representative of strong CYP3A4 inhibitors such as ketoconazole, posaconazole, clarithromycin, telithromycin, HIV protease inhibitors, and nefazodone. 12 200 mg QD for 4 days 40 mg on Day 4 > 36 Estimated minimum change. 22 10 100 mg QD for 4 days 40 mg on Day 4 > 14. 4 Grapefruit Juice The effect of amounts of grapefruit juice between those used in these two studies on lovastatin pharmacokinetics has not been studied. 10 200 mL of double-strength TID Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose lovastatin and 30 and 90 minutes following single dose lovastatin on Day 3. 80 mg single dose 15. 0 Grapefruit Juice 16 8 oz (about 250 mL) of single-strength Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and lovastatin was administered in the evening on Day 3. 40 mg single dose 1. 57 Cyclosporine 16 Not described Cyclosporine-treated patients with psoriasis or post kidney or heart transplant patients with stable graft function, transplanted at least 9 months prior to study. 10 mg QD for 10 days 5- to 8-fold ND ND = Analyte not determined. Number of Subjects Dosing of Coadministered Drug or Grapefruit Juice Dosing of Lovastatin AUC Ratio ( with / without coadministered drug ) No Effect = 1. 00 Total Lovastatin acid Lactone converted to acid by hydrolysis prior to analysis. Figure represents total unmetabolized acid and lactone. Diltiazem 10 120 mg BID for 14 days 20 mg 3. 57 Clinical Studies in Adults Lovastatin has been shown to reduce total-C and LDL-C in 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 to 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, lovastatin, administered in doses ranging from 10 mg q. , was compared to placebo. Lovastatin consistently and significantly decreased plasma total-C, LDL-C, total-C/HDL-C ratio and LDL-C/HDL-C ratio. In addition, lovastatin produced increases of variable magnitude in HDL-C, and modestly decreased VLDL-C and plasma TG (see Tables II through IV for dose response results). The results of a study in patients with primary hypercholesterolemia are presented in Table II. TABLE II Lovastatin vs. Placebo(Mean Percent Change from Baseline After 6 Weeks) DOSAGE N TOTAL - C LDL - C HDL - C LDL - C / HDL - C TOTAL - C / HDL - C TG. Placebo 33 -2 -1 -1 0 +1 +9 Lovastatin 10 mg q. 33 -16 -21 +5 -24 -19 -10 20 mg q. 33 -19 -27 +6 -30 -23 +9 10 mg b. 32 -19 -28 +8 -33 -25 -7 40 mg q. 33 -22 -31 +5 -33 -25 -8 20 mg b. 36 -24 -32 +2 -32 -24 -6 Lovastatin was compared to cholestyramine in a randomized open parallel study. The study was performed with patients with hypercholesterolemia who were at high risk of myocardial infarction. Summary results are presented in Table III. TABLE III Lovastatin vs. Cholestyramine(Percent Change from Baseline After 12 Weeks) TREATMENT N TOTAL - C ( mean ) LDL - C ( mean ) HDL - C ( mean ) LDL - C / HDL - C ( mean ) TOTAL - C / HDL - C ( mean ) VLDL - C ( median ) TG. ( mean ) Lovastatin 20 mg b. 85 -27 -32 +9 -36 -31 -34 -21 40 mg b. 88 -34 -42 +8 -44 -37 -31 -27 Cholestyramine 12 g b. 88 -17 -23 +8 -27 -21 +2 +11 Lovastatin was studied in controlled trials in hypercholesterolemic patients with well-controlled non-insulin dependent diabetes mellitus with normal renal function. The effect of lovastatin on lipids and lipoproteins and the safety profile of lovastatin were similar to that demonstrated in studies in nondiabetics. Lovastatin had no clinically important effect on glycemic control or on the dose requirement of oral hypoglycemic agents. Expanded Clinical Evaluation of Lovastatin (EXCEL) Study Lovastatin was compared to placebo in 8,245 patients with hypercholesterolemia (total-C 240 to 300 mg/dL [6. 2 mmol/L to 7. 6 mmol/L], LDL-C >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 lovastatin treated patients were dose-related and significantly different from placebo (p<=0. These results were sustained throughout the study. TABLE IV Lovastatin vs. Placebo(Percent Change from Baseline em dashAverage Values Between Weeks 12 and 48) * * DOSAGE N * * TOTAL - C ( mean ) LDL - C ( mean ) HDL - C ( mean ) LDL - C / HDL - C ( mean ) TOTAL - C / HDL - C ( mean ) TG. ( median ) Placebo 1663 +0. 6 +4 Lovastatin 20 mg q. 1642 -17 -24 +6. 6 -27 -21 -10 40 mg q. 1645 -22 -30 +7. 2 -34 -26 -14 20 mg b. 1646 -24 -34 +8. 6 -38 -29 -16 40 mg b. 1649 -29 -40 +9. 5 -44 -34 -19 Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), a double-blind, randomized, placebo-controlled, primary prevention study, demonstrated that treatment with lovastatin decreased the rate of acute major coronary events (composite endpoint of myocardial infarction, unstable angina, and sudden cardiac death) compared with placebo during a median of 5. 1 years of follow-up. Participants were middle-aged and elderly men (ages 45 to 73) and women (ages 55 to 73) without symptomatic cardiovascular disease with average to moderately elevated total-C and LDL-C, below average HDL-C, and who were at high risk based on elevated total-C/HDL-C. In addition to age, 63% of the participants had at least one other risk factor (baseline HDL-C <35 mg/dL, hypertension, family history, smoking and diabetes). AFCAPS/TexCAPS enrolled 6,605 participants (5,608 men, 997 women) based on the following lipid entry criteria: total-C range of 180 to 264 mg/dL, LDL-C range of 130 to 190 mg/dL, HDL-C of <=45 mg/dL for men and <=47 mg/dL for women, and TG of <=400 mg/dL. Participants were treated with standard care, including diet, and either lovastatin 20 to 40 mg daily (n= 3,304) or placebo (n= 3,301). Approximately 50% of the participants treated with lovastatin were titrated to 40 mg daily when their LDL-C remained >110 mg/dL at the 20-mg starting dose. Lovastatin reduced the risk of a first acute major coronary event, the primary efficacy endpoint, by 37% (lovastatin 3. 5%, placebo 5. 001; Figure 1). A first acute major coronary event was defined as myocardial infarction (54 participants on lovastatin, 94 on placebo) or unstable angina (54 vs. 80) or sudden cardiac death (8 vs. Furthermore, among the secondary endpoints, lovastatin reduced the risk of unstable angina by 32% (1. 023), of myocardial infarction by 40% (1. 002), and of undergoing coronary revascularization procedures (e. , coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 33% (3. Trends in risk reduction associated with treatment with lovastatin were consistent across men and women, smokers and non-smokers, hypertensives and non-hypertensives, and older and younger participants. Participants with >=2 risk factors had risk reductions (RR) in both acute major coronary events (RR 43%) and coronary revascularization procedures (RR 37%). Because there were too few events among those participants with age as their only risk factor in this study, the effect of lovastatin on outcomes could not be adequately assessed in this subgroup. Atherosclerosis In the Canadian Coronary Atherosclerosis Intervention Trial (CCAIT), the effect of therapy with lovastatin on coronary atherosclerosis was assessed by coronary angiography 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 to 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. 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 percent diameter stenosis of all lesions), or for most secondary QCA endpoints. Visual assessment by angiographers who formed a consensus opinion of overall angiographic change (Global Change Score) was also a secondary endpoint. By this endpoint, 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 lesions 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 to 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 intimalmedial thickness (IMT) of 12 measured segments. There was a significant regression of carotid lesions in patients receiving lovastatin alone compared to those receiving placebo alone (p=0. 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. Eye 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 were no clinically or statistically significant 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. Clinical Studies in Adolescent Patients Efficacy of Lovastatin in Adolescent Boys with Heterozygous Familial Hypercholesterolemia In a double-blind, placebo-controlled study, 132 boys 10 to 17 years of age (mean age 12. 7 yrs) with heterozygous familial hypercholesterolemia (heFH) were randomized to lovastatin (n=67) or placebo (n=65) for 48 weeks. Inclusion in the study required a baseline LDL-C level between 189 and 500 mg/dL and at least one parent with an LDL-C level >189 mg/dL. The mean baseline LDL-C value was 253. 1 mg/dL (range: 171 to 379 mg/dL) in the lovastatin group compared to 248. 2 mg/dL (range: 158. 5 mg/dL) in the placebo group. The dosage of lovastatin (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter. Lovastatin significantly decreased plasma levels of total-C, LDL-C and apolipoprotein B (see Table V). TABLE V Lipid - lowering Effects of Lovastatin in Adolescent Boys with Heterozygous Familial Hypercholesterolemia ( Mean Percent Change from Baseline at Week 48 in Intention - to - Treat Population ) DOSAGE N TOTAL - C LDL - C HDL - C TG. data presented as median percent changes Apolipoprotein B Placebo 61 -1. 4 Lovastatin 64 -19. 9 -21 The mean achieved LDL-C value was 190. 9 mg/dL (range: 108 to 336 mg/dL) in the lovastatin group compared to 244. 8 mg/dL (range: 135 to 404 mg/dL) in the placebo group. Efficacy of Lovastatin in Post-Menarchal Girls with Heterozygous Familial Hypercholesterolemia In a double-blind, placebo-controlled study, 54 girls 10 to 17 years of age who were at least 1 year post-menarche with heFH were randomized to lovastatin (n=35) or placebo (n=19) for 24 weeks. Inclusion in the study required a baseline LDL-C level of 160 to 400 mg/dL and a parental history of familial hypercholesterolemia. The mean baseline LDL-C value was 218. 3 mg/dL (range: 136. 7 mg/dL) in the lovastatin group compared to 198. 8 mg/dL (range: 151. 1 mg/dL) in the placebo group. The dosage of lovastatin (once daily in the evening) was 20 mg for the first 4 weeks, and 40 mg thereafter. Lovastatin significantly decreased plasma levels of total-C, LDL-C, and apolipoprotein B (see Table VI). * TABLE VI Lipid - lowering Effects of Lovastatin in Post - Menarchal Girls with Heterozygous Famillai Hypercholesterolemia ( Mean Percent Change from Baseline at Week 24 in Intention - to - Treat Population ) DOSAGE N TOTAL - C LDL - C HDL - C TG. * Apolipoprotein B Placebo 18 +3. 4 Lovastatin 35 -22. 4 The mean achieved LDL-C value was 154. 5 mg/dL (range: 82 to 286 mg/dL) in the lovastatin group compared to 203. 5 mg/dL (range: 135 to 304 mg/dL) in the placebo group. The safety and efficacy of doses above 40 mg daily have not been studied in children. The long-term efficacy of lovastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

Therapy with lovastatin tablets USP should be a component of multiple risk factor intervention in those individuals with dyslipidemia at risk for atherosclerotic vascular disease. Lovastatin tablets USP should be used in addition to a diet restricted in saturated fat and cholesterol as part of a treatment strategy to lower total-C and LDL-C to target levels when the response to diet and other nonpharmacological measures alone has been inadequate to reduce risk. Primary Prevention of Coronary Heart Disease In individuals without symptomatic cardiovascular disease, average to moderately elevated total-C and LDL-C and below average HDL-C, lovastatin tablets USP are indicated to reduce the risk of: -Myocardial infarction -Unstable angina -Coronary revascularization procedures (See CLINICAL PHARMACOLOGY, Clinical Studies Coronary Heart Disease Lovastatin tablets USP are indicated to slow the progression of coronary atherosclerosis in patients with coronary heart disease as part of a treatment strategy to lower total-C and LDL-C to target levels. Hypercholesterolemia 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. Lovastatin tablets USP are indicated as an adjunct to diet for the reduction of elevated total-C and LDL-C levels in patients with primary hypercholesterolemia (Types IIa and IIb 2 2 IDL = intermediate-density lipoprotein. Type Lipoproteins elevated Lipid Elevations major minor I chylomicrons TG up arrowarrowC IIa LDL C em dash IIb LDL,VLDL C TG III (rare) IDL C/TG em dash IV VLDL TG up arrowarrowC V (rare) chylomicrons,VLDL TG up arrowarrowC Adolescent Patients with Heterozygous Familial Hypercholesterolemia Lovastatin tablets USP are indicated as an adjunct to diet to reduce total-C, LDL-C and apolipoprotein B levels in adolescent boys and girls who are at least one year post-menarche, 10 to 17 years of age, with heFH if after an adequate trial of diet therapy the following findings are present: 1. LDL-C remains >189 mg/dL or 2. LDL-C remains >160 mg/dL and: there is a positive family history of premature cardiovascular disease or two or more other CVD risk factors are present in the adolescent patient General Recommendations 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 TG. For patients with TG less than 400 mg / / LDL-C = total-C en dash [0.2 × (TG) + HDL-C] For TG levels >400 mg/dL (>4.5 mmol/L), this equation is less accurate and LDL-C concentrations should be determined by ultracentrifugation. In hypertriglyceridemic patients, LDL-C may be low or normal despite elevated total-C. In such cases, lovastatin tablets USP are not indicated. The National Cholesterol Education Program (NCEP) Treatment Guidelines are summarized below: dagger dagger dagger dagger dagger dagger NCEP Treatment Guidelines : LDL - C Goals and Cutpoints for Therapeutic Lifestyle Changes and Drug Therapy in Different Risk Categories Risk Category LDL Goal ( mg / dL ) LDL Level at Which to Initiate Therapeutic Lifestyle Changes ( mg / dL ) LDL Level at Which to Consider Drug Therapy ( mg / dL ) CHD dagger <100 >=100 >=130 dagger dagger 2+ Risk factors <130 >=130 10-year risk 10 to 20%: >=130 0 to 1 Risk factor dagger dagger dagger <160 >=160 >=190 After the LDL-C goal has been achieved, if the TG is still >=200 mg/dL, non-HDL-C (total-C minus HDL-C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals for each risk category. At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug therapy at discharge if the LDL-C is >=130 mg/dL (see NCEP Guidelines above). Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels be used to initiate and assess treatment response. Only if LDL-C levels are not available, should the total-C be used to monitor therapy. Although lovastatin tablets USP may be useful to reduce elevated LDL-C levels in patients with combined hypercholesterolemia 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). 2 The NCEP classification of cholesterol levels in pediatric patients with a familial history of hypercholesterolemia or premature cardiovascular disease is summarized below: Category Total - C ( mg / dL ) LDL - C ( mg / dL ) Acceptable <170 <110 Borderline 170 to 199 110 to 129 High >=200 >=130 Children treated with lovastatin in adolescence should be re-evaluated in adulthood and appropriate changes made to their cholesterol-lowering regimen to achieve adult goals for LDL-C.

The patient should be placed on a standard cholesterol-lowering diet before receiving lovastatin tablets USP and should continue on this diet during treatment with lovastatin tablets USP (see NCEP Treatment Guidelines for details on dietary therapy). Lovastatin tablets USP should be given with meals. Adult Patients The usual recommended starting dose is 20 mg once a day given with the evening meal. The recommended dosing range of lovastatin is 10 to 80 mg / / (see NCEP Guidelines CLINICAL PHARMACOLOGY (see INDICATIONS AND USAGE Cholesterol levels should be monitored periodically and consideration should be given to reducing the dosage of lovastatin tablets if cholesterol levels fall significantly below the targeted range. Dosage in Patients taking Danazol, Diltiazem, Dronedarone or Verapamil In patients taking danazol, diltiazem, dronedarone or verapamil concomitantly with lovastatin, therapy should begin with 10 mg of lovastatin and should not exceed 20 mg / (see CLINICAL PHARMACOLOGY, Pharmacokinetics WARNINGS, Myopathy/Rhabdomyolysis PRECAUTIONS, Drug Interactions Other Drug Interactions Dosage in Patients taking Amiodarone In patients taking amiodarone concomitantly with lovastatin, the dose should not exceed 40 mg/day (see WARNINGS, Myopathy/Rhabdomyolysis PRECAUTIONS, Drug Interactions Other Drug Interactions Adolescent Patients (10 to 17 years of age) with Heterozygous Familial Hypercholesterolemia The recommended dosing range of lovastatin is 10 to 40 mg / / (see NCEP Pediatric Panel Guidelines 4 CLINICAL PHARMACOLOGY INDICATIONS AND USAGE Concomitant Lipid-Lowering Therapy Lovastatin tablets USP are effective alone or when used concomitantly with bile-acid sequestrants (see WARNINGS, Myopathy/Rhabdomyolysis PRECAUTIONS, Drug Interactions Dosage in Patients with Renal Insufficiency In patients with severe renal insufficiency (creatinine clearance <30 mL / / (see CLINICAL PHARMACOLOGY WARNINGS, Myopathy/Rhabdomyolysis

Phase III Clinical Studies In Phase III controlled clinical studies involving 613 patients treated with lovastatin, the adverse experience profile was similar to that shown below for the 8,245-patient EXCEL study (see Expanded Clinical Evaluation of Lovastatin [EXCEL] Study Persistent increases of serum transaminases have been noted (see WARNINGS, Liver Dysfunction (see WARNINGS, Myopathy/Rhabdomyolysis Expanded Clinical Evaluation of Lovastatin (EXCEL) Study Lovastatin was compared to placebo in 8,245 patients with hypercholesterolemia (total-C 240 to 300 mg / / Placebo ( N = 1663 ) % Lovastatin 20 mg q . p . m . ( N = 1642 ) % Lovastatin 40 mg q . p . m . ( N = 1645 ) % Lovastatin 20 mg b . i . d . ( N = 1646 ) % Lovastatin 40 mg b . i . d . ( N = 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 Musculoskeletal Muscle cramps 0.5 0.6 0.8 1.1 1.0 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: Gastrointestinal: Musculoskeletal: Nervous System/Psychiatric: Skin: Special Senses: In the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical Studies Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) In AFCAPS/TexCAPS (see CLINICAL PHARMACOLOGY, Clinical Studies (see ADVERSE REACTIONS, Expanded Clinical Evaluation of Lovastatin (EXCEL) Study 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 gemfibrozil to therapy with lovastatin is not associated with greater reduction in LDL-C than that achieved with lovastatin alone. In uncontrolled clinical studies, most of the patients who have developed myopathy were receiving concomitant therapy with cyclosporine, gemfibrozil or niacin (nicotinic acid). The combined use of lovastatin with cyclosporine or gemfibrozil should be avoided. Caution should be used when prescribing other fibrates or lipid-lowering doses (>=1 g/day) of niacin with lovastatin (see WARNINGS, Myopathy/Rhabdomyolysis 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: There have been rare reports of immune-mediated necrotizing myopathy associated with statin use (see WARNINGS, Myopathy/Rhabdomyolysis). Neurological: There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). Hypersensitivity Reactions: Gastrointestinal: Skin: / / Reproductive: Eye: Laboratory Abnormalities: Respiratory Adolescent Patients (ages 10 to 17 years) In a 48-week controlled study in adolescent boys with heFH (n=132) and a 24-week controlled study in girls who were at least 1 year post-menarche with heFH (n=54), the safety and tolerability profile of the groups treated with lovastatin (10 to 40 mg daily) was generally similar to that of the groups treated with placebo (see CLINICAL PHARMACOLOGY, Clinical Studies in Adolescent Patients PRECAUTIONS, Pediatric Use

Hypersensitivity to any component of this medication. Active liver disease or unexplained persistent elevations of serum transaminases (see WARNINGS Concomitant administration with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and cobicistat-containing products) (see WARNINGS, Myopathy/Rhabdomyolysis Pregnancy and lactation (see PRECAUTIONS, Pregnancy Nursing Mothers 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 lovastatin to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway, lovastatin is contraindicated during pregnancy and in nursing mothers. Lovastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive. (see PRECAUTIONS, Pregnancy

WARNINGS
Myopathy/Rhabdomyolysis Lovastatin, 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. The risk of myopathy/rhabdomyolysis is dose related. All patients starting therapy with lovastatin, or whose dose of lovastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persists after discontinuing lovastatin. Lovastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. Many of the patients who have developed rhabdomyolysis on therapy with lovastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. Lovastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Lovastatin therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy. The risk of myopathy/rhabdomyolysis is increased by concomitant use of lovastatin with the following: Strong inhibitors of CYP3A4 Lovastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of cytochrome P450 3A4 (CYP3A4). Certain drugs which inhibit this metabolic pathway can raise the plasma levels of lovastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, posaconazole, voriconazole, the macrolide antibiotics erythromycin and clarithromycin, the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, the antidepressant nefazodone, or cobicistat-containing products. Combination of these drugs with lovastatin is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is unavoidable, therapy with lovastatin should be suspended during the course of treatment (see CONTRAINDICATIONS PRECAUTIONS, Drug Interactions Gemfibrozil The combined use of lovastatin with gemfibrozil should be avoided. Other lipid-lowering drugs (other fibrates or >=1 g/day of niacin) Caution should be used when prescribing other fibrates or lipid-lowering doses (>=1 g/day) of niacin with lovastatin, as these agents can cause myopathy when given alone. The benefit of further alterations in lipid levels by the combined use of lovastatin with other fibrates or niacin should be carefully weighed against the potential risks of these combinations. Cyclosporine The use of lovastatin with cyclosporine should be avoided. Danazol, diltiazem, dronedarone or verapamil with higher doses of lovastatin The dose of lovastatin should not exceed 20 mg daily in patients receiving concomitant medication with danazol, diltiazem, dronedarone, or verapamil. Amiodarone The dose of lovastatin should not exceed 40 mg daily in patients receiving concomitant medication with amiodarone. Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with lovastatin coadministered with colchicine, and caution should be exercised when prescribing lovastatin with colchicine (see PRECAUTIONS, Drug Interactions Ranolazine The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of ranolazine. Dose adjustment of lovastatin may be considered during coadministration with ranolazine. Prescribing recommendations for interacting agents are summarized in Table VII (see also CLINICAL PHARMACOLOGY, Pharmacokinetics PRECAUTIONS, Drug Interactions DOSAGE AND ADMINISTRATION ). Table VII Drug Interactions Associated with Increased Risk of Myopathy / Rhabdomyolysis Interacting Agents Prescribing Recommendations Strong CYP3A4 inhibitors, e.g.: Contraindicated with lovastatin Gemfibrozil Avoid with lovastatin Danazol Do not exceed 20 mg lovastatin daily Amiodarone Do not exceed 40 mg lovastatin daily Grapefruit juice Avoid grapefruit juice Immune-Mediated Necrotizing Myopathy There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiation of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM. Liver Dysfunction 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 (see CLINICAL PHARMACOLOGY, Clinical Studies (see ADVERSE REACTIONS In AFCAPS/TexCAPS, the number of participants with consecutive elevations of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (> 3 times the upper limit of normal), over a median of 5.1 years of follow-up, was not significantly different between the lovastatin and placebo groups (18 [0.6%] vs. 11 [0.3%]). The starting dose of lovastatin was 20 mg/day; 50% of the lovastatin treated participants were titrated to 40 mg/day at Week 18. Of the 18 participants on lovastatin with consecutive elevations of either ALT or AST, 11 (0.7%) elevations occurred in participants taking 20 mg/day, while 7 (0.4%) elevations occurred in participants titrated to 40 mg/day. Elevated transaminases resulted in discontinuation of 6 (0.2%) participants from therapy in the lovastatin group (n=3,304) and 4 (0.1%) in the placebo group (n=3,301). It is recommended that liver enzyme tests be obtained prior to initiating therapy with lovastatin and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including lovastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with lovastatin, promptly interrupt therapy. If an alternate etiology is not found do not restart lovastatin. 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 contraindications to the use of lovastatin. Moderate (less than three times the upper limit of normal) elevations of serum transaminases have been reported following therapy with lovastatin (see ADVERSE REACTIONS
OVERDOSAGE
After oral administration of lovastatin to mice, the median lethal dose observed was >15 g / 2 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 to 6 g. Until further experience is obtained, no specific treatment of overdosage with lovastatin can be recommended. The dialyzability of lovastatin and its metabolites in man is not known at present.

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