ease 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.

ed 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. in most cases, muscle symptoms and ck increases resolved when treatment was promptly discontinued. periodic ck determinations may be considered in patients starting therapy with lovastatin or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy. many of the patients who have developed rhabdomyolysis on therapy with 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. the benefits of the use of lovastatin in patients receiving danazol, diltiazem, dronedarone, or verapamil should be carefully weighed against the risks of these combinations. amiodarone the dose of lovastatin should not exceed 40 mg daily in patients receiving concomitant medication with amiodarone. the combined use of lovastatin at doses higher than 40 mg daily with amiodarone should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy. the risk of myopathy/rhabdomyolysis is increased when amiodarone is used concomitantly with higher doses of a closely related member of the hmg-coa reductase inhibitor class. 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.: ketoconazole itraconazole posaconazole voriconazole erythromycin clarithromycin telithromycin hiv protease inhibitors boceprevir telaprevir nefazodone cobicistat-containing products contraindicated with lovastatin gemfibrozil cyclosporine avoid with lovastatin danazol diltiazem dronedarone verapamil 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 ). when the drug was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. the increases 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 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 lovastatin, symptomatic liver disease has been reported rarely at all dosages (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 ). these changes appeared soon after initiation of therapy with lovastatin, were often transient, were not accompanied by any symptoms and interruption of treatment was not required.

eeks 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 ).

eriences 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 ).

olism of ldl-c. apolipoprotein b also falls during treatment with lovastatin. 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. pharmacokinetics lovastatin is a lactone which is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a strong inhibitor of hmg-coa reductase. inhibition of hmg-coa reductase is the basis for an assay in pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of lovastatin. following an oral dose of 14 c-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 radioactivity (lovastatin plus 14 c-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 non-target 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 extensive hepatic extraction of lovastatin, 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 variation, 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 β-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 β-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 conditions, 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 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 and precautions, drug interactions ). lovastatin is a substrate for cytochrome p450 isoform 3a4 (cyp3a4) (see precautions, drug interactions ). grapefruit juice contains one or more components that inhibit cyp3a4 and can increase the plasma concentrations of drugs metabolized by cyp3a4. in one study 1 , 10 subjects consumed 200 ml of double-strength grapefruit juice (one can of frozen concentrate diluted with one rather than 3 cans of water) three times daily for 2 days and an additional 200 ml double-strength grapefruit juice together with and 30 and 90 minutes following a single dose of 80 mg lovastatin on the third day. this regimen of grapefruit juice resulted in a mean increase in the serum concentration of lovastatin and its β-hydroxyacid metabolite (as measured by the area under the concentration-time curve) of 15-fold and 5-fold, respectively [as measured using a chemical assay — high performance liquid chromatography]. in a second study, 15 subjects consumed one 8 oz glass of single-strength grapefruit juice (one can of frozen concentrate diluted with 3 cans of water) with breakfast for 3 consecutive days and a single dose of 40 mg lovastatin in the evening of the third day. this regimen of grapefruit juice resulted in a mean increase in the plasma concentration (as measured by the area under the concentration-time curve) of active and total hmg-coa reductase inhibitory activity [using an enzyme inhibition assay both before (for active inhibitors) and after (for total inhibitors) base hydrolysis] of 1.34-fold and 1.36-fold, respectively, and of lovastatin and its β-hydroxyacid metabolite [measured using a chemical assay — liquid chromatography/tandem mass spectrometry — different from that used in the first 1 study] of 1.94-fold and 1.57-fold, respectively. the effect of amounts of grapefruit juice between those used in these two studies on lovastatin pharmacokinetics has not been studied. 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 β-hydroxyacid of lovastatin. gemfibrozil 11 600 mg bid for 3 days 40 mg 0.96 2.80 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 > 14.8 15.4 grapefruit juice the effect of amounts of grapefruit juice between those used in these two studies on lovastatin pharmacokinetics has not been studied. (high dose) 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 15.3 5.0 grapefruit juice (low dose) 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. for 4 days 40 mg single dose 1.94 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.p.m. to 40 mg b.i.d., 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.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 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.i.d. 85 -27 -32 +9 -36 -31 -34 -21 40 mg b.i.d. 88 -34 -42 +8 -44 -37 -31 -27 cholestyramine 12 g b.i.d. 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≤0.001). these results were sustained throughout the study. table iv lovastatin vs. placebo (percent change from baseline —average values between weeks 12 and 48) ** patients enrolled 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 +0.7 +0.4 +2.0 +0.2 +0.6 +4 lovastatin 20 mg q.p.m. 1642 -17 -24 +6.6 -27 -21 -10 40 mg q.p.m. 1645 -22 -30 +7.2 -34 -26 -14 20 mg b.i.d. 1646 -24 -34 +8.6 -38 -29 -16 40 mg b.i.d. 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 5.5%; p<0.001; 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. 9). furthermore, among the secondary endpoints, lovastatin reduced the risk of unstable angina by 32% (1.8 vs. 2.6%; p=0.023), of myocardial infarction by 40% (1.7 vs. 2.9%; p=0.002), and of undergoing coronary revascularization procedures (e.g., coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 33% (3.2 vs. 4.8%; p=0.001). 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. 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 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=0.001). 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). 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 to 413.5 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 -1.1 -1.4 -2.2 -1.4 -4.4 lovastatin 64 -19.3 -24.2 +1.1 -1.9 -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: 136.3 to 363.7 mg/dl) in the lovastatin group compared to 198.8 mg/dl (range: 151.1 to 283.1 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). * data presented as median percent changes 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 +3.6 +2.5 +4.8 -3.0 +6.4 lovastatin 35 -22.4 -29.2 +2.4 -22.7 -24.4 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. figure 1

tatin had high selectivity for the liver, where it achieved substantially higher concentrations than in non-target 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 extensive hepatic extraction of lovastatin, 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 variation, 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 β-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 β-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 conditions, 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 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 and precautions, drug interactions ). lovastatin is a substrate for cytochrome p450 isoform 3a4 (cyp3a4) (see precautions, drug interactions ). grapefruit juice contains one or more components that inhibit cyp3a4 and can increase the plasma concentrations of drugs metabolized by cyp3a4. in one study 1 , 10 subjects consumed 200 ml of double-strength grapefruit juice (one can of frozen concentrate diluted with one rather than 3 cans of water) three times daily for 2 days and an additional 200 ml double-strength grapefruit juice together with and 30 and 90 minutes following a single dose of 80 mg lovastatin on the third day. this regimen of grapefruit juice resulted in a mean increase in the serum concentration of lovastatin and its β-hydroxyacid metabolite (as measured by the area under the concentration-time curve) of 15-fold and 5-fold, respectively [as measured using a chemical assay — high performance liquid chromatography]. in a second study, 15 subjects consumed one 8 oz glass of single-strength grapefruit juice (one can of frozen concentrate diluted with 3 cans of water) with breakfast for 3 consecutive days and a single dose of 40 mg lovastatin in the evening of the third day. this regimen of grapefruit juice resulted in a mean increase in the plasma concentration (as measured by the area under the concentration-time curve) of active and total hmg-coa reductase inhibitory activity [using an enzyme inhibition assay both before (for active inhibitors) and after (for total inhibitors) base hydrolysis] of 1.34-fold and 1.36-fold, respectively, and of lovastatin and its β-hydroxyacid metabolite [measured using a chemical assay — liquid chromatography/tandem mass spectrometry — different from that used in the first 1 study] of 1.94-fold and 1.57-fold, respectively. the effect of amounts of grapefruit juice between those used in these two studies on lovastatin pharmacokinetics has not been studied. 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 β-hydroxyacid of lovastatin. gemfibrozil 11 600 mg bid for 3 days 40 mg 0.96 2.80 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 > 14.8 15.4 grapefruit juice the effect of amounts of grapefruit juice between those used in these two studies on lovastatin pharmacokinetics has not been studied. (high dose) 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 15.3 5.0 grapefruit juice (low dose) 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. for 4 days 40 mg single dose 1.94 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.p.m. to 40 mg b.i.d., 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.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 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.i.d. 85 -27 -32 +9 -36 -31 -34 -21 40 mg b.i.d. 88 -34 -42 +8 -44 -37 -31 -27 cholestyramine 12 g b.i.d. 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≤0.001). these results were sustained throughout the study. table iv lovastatin vs. placebo (percent change from baseline —average values between weeks 12 and 48) ** patients enrolled 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 +0.7 +0.4 +2.0 +0.2 +0.6 +4 lovastatin 20 mg q.p.m. 1642 -17 -24 +6.6 -27 -21 -10 40 mg q.p.m. 1645 -22 -30 +7.2 -34 -26 -14 20 mg b.i.d. 1646 -24 -34 +8.6 -38 -29 -16 40 mg b.i.d. 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 5.5%; p<0.001; 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. 9). furthermore, among the secondary endpoints, lovastatin reduced the risk of unstable angina by 32% (1.8 vs. 2.6%; p=0.023), of myocardial infarction by 40% (1.7 vs. 2.9%; p=0.002), and of undergoing coronary revascularization procedures (e.g., coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 33% (3.2 vs. 4.8%; p=0.001). 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. 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 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=0.001). 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). 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 to 413.5 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 -1.1 -1.4 -2.2 -1.4 -4.4 lovastatin 64 -19.3 -24.2 +1.1 -1.9 -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: 136.3 to 363.7 mg/dl) in the lovastatin group compared to 198.8 mg/dl (range: 151.1 to 283.1 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). * data presented as median percent changes 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 +3.6 +2.5 +4.8 -3.0 +6.4 lovastatin 35 -22.4 -29.2 +2.4 -22.7 -24.4 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. figure 1

1 kantola, t, et al., clin pharmacol ther 1998; 63(4): 397-402 3 manson, j.m., freyssinges,c.ducrocq, m.b., stephenson, w.p., postmarketing surveillance of lovastatin and simvastatin exposure during pregnancy. reproductive toxicology. 10(6):439-446, 1996. 4 national cholesterol education program (ncep): highlights of the report of the expert panel on blood cholesterol levels in children and adolescents. pediatrics . 89(3):495-501. 1992. manufactured by: lupin limited goa 403 722 india for bluepoint laboratories revised: 01/2021 id#: 266229