LOVASTATIN- lovastatin tablet 
Direct_Rx

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LOVASTATIN

DESCRIPTION SECTION

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:

[Structural Formula]

Lovastatin is a white, nonhygroscopic crystalline powder that is insoluble in water and sparingly soluble in ethanol, methanol, and acetonitrile.

Lovastatin tablets 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: lactose monohydrate, magnesium stearate, microcrystalline cellulose, poloxamer, pregelatinized starch, sodium starch glycolate, butylated hydroxyanisole and talc. Butylated hydroxyanisole (BHA) is added as a preservative.

CLINICAL PHARMACOLOGY SECTION

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 both normal and 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/or increased catabolism 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.

____________________________________

1 Kantola, T, et al., Clin Pharmacol Ther 1998; 63(4):397-402.

[Table I]

* Results based on a chemical assay.

† Lovastatin acid refers to the β-hydroxyacid of lovastatin.

‡ 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.

§ Estimated minimum change.

¶ The effect of amounts of grapefruit juice between those used in these two studies on lovastatin pharmacokinetics has not been studied.

# 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.

Þ 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.

ß Cyclosporine-treated patients with psoriasis or post kidney or heart transplant patients with stable graft function, transplanted at least 9 months prior to study.

à ND = Analyte not determined.

è Lactone converted to acid by hydrolysis prior to analysis. Figure represents total unmetabolized acid and lactone.

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 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 TRIG.
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) TRIG.

(median)
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 240-300 mg/dL [6.2 mmol/L-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) TRIG.
(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.

[Figure 1]

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)

*data presented as median percent changes

DOSAGE N TOTAL-C LDL-C HDL-C TG. * 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: 151.5 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).

TABLE VI Lipid-lowering Effects of Lovastatin in Post-menarchal Girls with Heterozygous Familial Hypercholesterolemia (Mean Percent Change from Baseline at Week 24 in Intention-to-Treat Population)

*data presented as median percent changes

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.

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 intimal-

medial 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

INDICATIONS & USAGE SECTION

Therapy with lovastatin should be a component of multiple risk factor intervention in those individuals with dyslipidemia at risk for atherosclerotic vascular disease. Lovastatin 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 is indicated to reduce the risk of:

Myocardial infarction
Unstable angina
Coronary revascularization procedures

(See CLINICAL PHARMACOLOGY, CLINICAL STUDIES.)

Coronary Heart Disease

Lovastatin is 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 artherosclerotic vascular disease due to hypercholesterolemia. Lovastatin is 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.

Adolescent Patients with Heterozygous Familial Hypercholesterolemia

Lovastatin is 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:

LDL-C remains >189 mg/dL or
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 is 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 0-1 risk factor have a 10-year risk <10%; thus, 10-year risk assessment in people with 0-1 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
(100-129: drug optional) ††
2+ Risk factors
(10 year risk ≤20%) <130 ≥130 10-year risk 10-20%: ≥130
10-year risk <10%: ≥160
0-1 Risk factor ††† <160 ≥160 ≥190
(160-189: LDL-lowering drug optional)

2 Classification of Hyperlipoproteinemias
Lipid Elevations
Type Lipoproteins
elevated 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
IDL = intermediate-density lipoprotein.

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 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). ***

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 170-199 110-129
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.

CONTRAINDICATIONS SECTION

WARNINGS SECTION

PRECAUTIONS SECTION

ADVERSE REACTIONS SECTION

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.

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 240-300 mg/dL [6.2-7.8 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.

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 ).

OVERDOSAGE SECTION

After oral administration of lovastatin to mice, the median lethal dose observed was >15 g/m 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.

DOSAGE & ADMINISTRATION SECTION

The patient should be placed on a standard cholesterol-lowering diet before receiving lovastatin and should continue on this diet during treatment with lovastatin (see NCEP Treatment Guidelines for details on dietary therapy). Lovastatin 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 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. A starting dose of 10 mg may be considered for patients requiring smaller reductions. Adjustments should be made at intervals of 4 weeks or more.

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

DOSAGE FORMS & STRENGTHS SECTION

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 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 ††, 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 may be considered for patients requiring smaller reductions. Adjustments should be made at intervals of 4 weeks or more.

Concomitant Lipid-Lowering Therapy

Lovastatin is 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 ).

HOW SUPPLIED SECTION

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

941

LOVASTATIN 
lovastatin tablet
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:61919-941(NDC:61442-143)
Route of AdministrationORAL
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
LOVASTATIN (UNII: 9LHU78OQFD) (LOVASTATIN - UNII:9LHU78OQFD) LOVASTATIN40 mg
Inactive Ingredients
Ingredient NameStrength
LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
MAGNESIUM STEARATE (UNII: 70097M6I30)  
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)  
POLOXAMER 188 (UNII: LQA7B6G8JG)  
SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)  
STARCH, CORN (UNII: O8232NY3SJ)  
TALC (UNII: 7SEV7J4R1U)  
BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U)  
Product Characteristics
ColorwhiteScoreno score
ShapeROUNDSize10mm
FlavorImprint Code CTI;143
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:61919-941-9090 in 1 BOTTLE; Type 0: Not a Combination Product09/18/2019
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA07599101/01/2014
Labeler - Direct_Rx (079254320)
Registrant - Direct_Rx (079254320)
Establishment
NameAddressID/FEIBusiness Operations
Direct_Rx079254320repack(61919-941)

Revised: 1/2023
Document Id: f21620a9-ccb5-d6aa-e053-2a95a90a7ced
Set id: 8e5a0177-4804-4638-ad82-c8877653b232
Version: 5
Effective Time: 20230112
 
Direct_Rx