LOVASTATIN

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 β-hydroxyacid form. This is a principal metabolite and 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. Lovastatin is [1 S -[1α( R * ),3α,7β,8β(2 S * ,4 S * ),8aβ]]-1,2,3,7, 8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2 H -pyran-2-yl)ethyl]-1-naphthalenyl 2-methylbutanoate. The empirical formula of lovastatin is C 24 H 36 O 5 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. Lovastatin tablets USP 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: D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, lactose anhydrous, lactose monohydrate, magnesium stearate, microcrystalline cellulose and pregelatinized corn starch. Butylated hydroxyanisole (BHA) is added as a preservative. lovastatin

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 ), when the response to diet restricted in saturated fat and cholesterol and to other nonpharmacological measures alone has been inadequate. 2 Classification of Hyperlipoproteinemias IDL = intermediate-density lipoprotein. Type Lipoproteins elevated Lipid Elevations major minor I chylomicrons TG ↑→C IIa LDL C — IIb LDL,VLDL C TG III (rare) IDL C/TG — IV VLDL TG ↑→C V (rare) chylomicrons,VLDL TG ↑→C 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 / dL (<4.5 mmol / L), LDL-C can be estimated using the following equation: LDL-C = total-C – [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: † CHD, coronary heart disease † † Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C level of <100 mg/dL cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL-C, e.g., nicotinic acid or fibrate. Clinical judgment also may call for deferring drug therapy in this subcategory. † † † Almost all people with 0 to 1 risk factor have a 10-year risk <10%; thus, 10-year risk assessment in people with 0 to 1 risk factor is not necessary. 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 † or CHD risk equivalents (10-year risk >20%) <100 ≥100 ≥130 (100 to 129: drug optional) † † 2+ Risk factors (10-year risk ≤20%) <130 ≥130 10-year risk 10 to 20%: ≥130 10-year risk <10%: ≥160 0 to 1 Risk factor † † † <160 ≥160 ≥190 (160 to 189: LDL-lowering drug optional) 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 / 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 CLINICAL PHARMACOLOGY ). Patients requiring reductions in LDL-C of 20% or more to achieve their goal (see INDICATIONS AND USAGE ) should be started on 20 mg/day of lovastatin tablets. A starting dose of 10 mg of lovastatin may be considered for patients requiring smaller reductions. Adjustments should be made at intervals of 4 weeks or more. 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 / day (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 and 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 / day; the maximum recommended dose is 40 mg / day. Doses should be individualized according to the recommended goal of therapy (see NCEP Pediatric Panel Guidelines 4 , CLINICAL PHARMACOLOGY , and INDICATIONS AND USAGE ). Patients requiring reductions in LDL-C of 20% or more to achieve their goal should be started on 20 mg/day of lovastatin. A starting dose of 10 mg of lovastatin may be considered for patients requiring smaller reductions. Adjustments should be made at intervals of 4 weeks or more. Concomitant Lipid-Lowering Therapy Lovastatin tablets USP are effective alone or when used concomitantly with bile-acid sequestrants (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions ). 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, Myopathy/Rhabdomyolysis ).

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 and 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. If the patient becomes pregnant while taking this drug, lovastatin should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus (see PRECAUTIONS, Pregnancy ).

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 ). About 11% of patients had elevations of CK levels of at least twice the normal value on one or more occasions. The corresponding values for the control agent cholestyramine was 9 percent. This was attributable to the noncardiac fraction of CK. Large increases in CK have sometimes been reported (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 / dL [6.2 to 7.8 mmol / L]) in the randomized, double-blind, parallel, 48-week EXCEL study. Clinical adverse experiences reported as possibly, probably or definitely drug-related in ≥1% in any treatment group are shown in the table below. For no event was the incidence on drug and placebo statistically different. 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: 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. 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 lovastatin. The value for the placebo group was 2.5%. Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) In AFCAPS/TexCAPS (see CLINICAL PHARMACOLOGY, Clinical Studies ) involving 6,605 participants treated with 20 to 40 mg/day of lovastatin (n=3,304) or placebo (n=3,301), the safety and tolerability profile of the group treated with lovastatin was comparable to that of the group treated with placebo during a median of 5.1 years of follow-up. The adverse experiences reported in AFCAPS/TexCAPS were similar to those reported in EXCEL (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: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use (see WARNINGS, Myopathy/Rhabdomyolysis). Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, dizziness, vertigo, paresthesia, peripheral neuropathy, peripheral nerve palsy, psychic disturbances, anxiety, insomnia, depression. 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: 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, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, 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, fatal and non-fatal hepatic failure. 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, γ-glutamyl transpeptidase, and bilirubin; thyroid function abnormalities. Respiratory : interstitial lung disease 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 and PRECAUTIONS, Pediatric Use ).