LOVASTATIN
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lovastatin tablet
International Labs, Inc.
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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-methylglutarylcoenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate limiting step in the biosynthesis of cholesterol. Lovastatin is [1S-[1α(R*),3α,7β,8β(2S*,4S*), 8aβ]]-1,2,3,7, 8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl 2-methylbutanoate. The empirical formula of lovastatin is C24H36O5 and its molecular weight is 404.55. Its structural formula is:
Lovastatin is a white, nonhygroscopic crystalline powder that is insoluble in water and sparingly soluble in ethanol, methanol, and acetonitrile. 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: D and C Yellow No. 10, FD and C Blue No. 2, lactose anhydrous, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch. Butylated hydroxyanisole (BHA) is added as a preservative.
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 (HDLC) 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 substantially during treatment with lovastatin. Since each LDL particle contains one molecule of apolipoprotein B, and since little apolipoprotein B is found in other lipoproteins, this strongly suggests that lovastatin does not merely cause cholesterol to be lost from LDL, but also reduces the concentration of circulating LDL particles. In addition, lovastatin can produce increases of variable magnitude in HDL-C, and modestly reduces VLDL-C and plasma triglycerides (TG) (see Tables I-III under Clinical Studies). The effects of lovastatin on Lp(a), fibrinogen, and certain other independent biochemical risk markers for coronary heart disease are unknown. 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 potent 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 14C-labeled lovastatin in man, 10% of the dose was excreted in urine and 83% in feces. The latter represents absorbed drug equivalents excreted in bile, as well as any unabsorbed drug. Plasma concentrations of total radioactivity (lovastatin plus 14C-metabolites) peaked at 2 hours and declined rapidly to about 10% of peak by 24 hours postdose. Absorption of lovastatin, estimated relative to an intravenous reference dose, in each of four animal species tested, averaged about 30% of an oral dose. In animal studies, after oral dosing, lovastatin had high selectivity for the liver, where it achieved substantially higher concentrations than in 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 (greater than 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 10-30 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 70-78 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 18-30 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. Potent 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**, 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** 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.
Clinical Studies in Adults
Lovastatin has been shown to be highly effective in reducing 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 4-6 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 LDLC/ HDL-C ratio. In addition, lovastatin produced increases of variable magnitude in HDL-C, and modestly decreased VLDL-C and plasma TG (see Tables I through III for dose response results). The results of a study in patients with primary hypercholesterolemia are presented in Table I.
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 II.
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 240-300 mg/dL [6.2 mmol/L - 7.6 mmol/L], LDL-C greater than 160 mg/dL [4.1 mmol/L]) in the randomized, double-blind, parallel, 48-week EXCEL study. All changes in the lipid measurements (Table III) in lovastatin treated patients were dose-related and significantly different from placebo (p less than or equal to 0.001). These results were sustained throughout the study.
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 |
**Patients enrolled
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 45-73) and women (ages 55-73) 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 less than 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 180-264 mg/dL, LDL-C range of 130-190 mg/dL, HDL-C of less than or equal to 45 mg/dL for men and less than or equal to 47 mg/dL for women, and TG of less than or equal to 400 mg/dL. Participants were treated with standard care, including diet, and either lovastatin 20-40 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 greater than 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 less than 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 R 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 20-80 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 10-40 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 10-17 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- 379 mg/dL) in the lovastatin group compared to 248.2 mg/dL (range: 158.5-413.5 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 IV).
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 |
*data presented as median percent changes
The mean achieved LDL-C value was 190.9 mg/dL (range: 108-336 mg/dL) in the lovastatin group compared to 244.8 mg/dL (range: 135-404 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 10-17 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 160-400 mg/dL and a parental history of familial hypercholesterolemia. The mean baseline LDL-C value was 218.3 mg/dL (range: 136.3-363.7 mg/dL) in the lovastatin group compared to 198.8 mg/dL (range: 151.1-283.1 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 V).
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 |
*data presented as median percent changes
The mean achieved LDL-C value was 154.5 mg/dL (range: 82-286 mg/dL) in the lovastatin group compared to 203.5 mg/dL (range: 135-304 mg/dL) in the placebo group. The safety and efficacy of doses above 40 mg daily have not been studied in children. The long-term efficacy of lovastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.
Therapy with lovastatin tablets should be a component of multiple risk factor intervention in those individuals with dyslipidemia at risk for atherosclerotic vascular disease. Lovastatin tablets should be used in addition to a diet restricted in saturated fat and cholesterol as part of a treatment strategy to lower total-C and LDL-C to target levels when the response to diet and other nonpharmacological measures alone has been inadequate to reduce risk.
Primary Prevention of Coronary Heart Disease
In individuals without symptomatic cardiovascular disease, average to moderately elevated total-C and LDL-C, and below average HDL-C, lovastatin tablets are indicated to reduce the risk of:
- Myocardial infarction
- Unstable angina
- Coronary revascularization procedures
(See CLINICAL PHARMACOLOGY, Clinical Studies.)
Coronary Heart Disease
Lovastatin tablets are indicated to slow the progression of coronary atherosclerosis in patients with coronary heart disease as part of a treatment strategy to lower total-C and LDL-C to target levels.
Hypercholesterolemia
Therapy with lipid-altering agents should be a component of multiple risk factor intervention in those individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Lovastatin tablets 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***), when the response to diet restricted in saturated fat and cholesterol and to other nonpharmacological measures alone has been inadequate.
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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
Adolescent Patients with Heterozygous Familial Hypercholesterolemia
Lovastatin tablets 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, 10-17 years of age, with heFH if after an adequate trial of diet therapy the following findings are present:
1. LDL-C remains greater than 189 mg/dL or
2. LDL-C remains greater than160 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 (less than 4.5 mmol/L), LDL-C can be estimated using the following equation: LDL-C = total-C – [0.2 x (TG) + HDL-C]
For TG levels greater than 400 mg/dL (greater than4.5 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 are not indicated. The National Cholesterol Education Program (NCEP) Treatment Guidelines are summarized below:
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 rick equivalence (10-year risk less than 20%) | less than 100 | ≥100 | ≥130 (100-129:drug optional)†† |
2+Risk Factors (10-year risk ≤20%) | less than 130 | ≥130 | 10-year risk 10-20%:≥130 10-year risk less than 10%:≥160 |
0-1 Risk Factor††† | less than 160 | ≥160 | ≥190 160-189:LDL-lowering drug optional) |
† CHD, coronary heart disease
†† Some authorities recommend use of
LDL-lowering drugs in this category if an LDL-C level of less than 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 less than
10%; thus, 10-year risk assessment in people with 0-1 risk factor is not
necessary.
After the LDL-C goal has been achieved, if the TG is still ≥200 mg/dL, non-HDL-C (total-C minus HDLC) 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 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 Borderline High | less than 170 170-199 ≥200 | less than 110 110-129 ≥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.
Myopathy/Rhabdomyolysis
Lovastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.
As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related. In a clinical study (EXCEL) in which patients were carefully monitored and some interacting drugs were excluded, there was one case of myopathy among 4933 patients randomized to lovastatin 20- 40 mg daily for 48 weeks, and 4 among 1649 patients randomized to 80 mg daily.
All patients starting therapy with lovastatin, or whose dose of lovastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. 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. Therapy with lovastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.
The risk of myopathy/rhabdomyolysis is increased by concomitant use of lovastatin with the following:
Potent inhibitors of CYP3A4: Lovastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of cytochrome P450 3A4 (CYP3A4). When lovastatin is used with a potent inhibitor of CYP3A4, elevated plasma levels of HMG-CoA reductase inhibitory activity can increase the risk of myopathy and rhabdomyolysis, particularly with higher doses of lovastatin.
The use of lovastatin concomitantly with the potent CYP3A4 inhibitors itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, or large quantities of grapefruit juice (>1 quart daily) should be avoided. Concomitant use of other medicines labeled as having a potent inhibitory effect on CYP3A4 should be avoided unless the benefits of combined therapy outweigh the increased risk. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with lovastatin should be suspended during the course of treatment.
Gemfibrozil, particularly with higher doses of lovastatin: The dose of lovastatin should not exceed 20 mg daily in patients receiving concomitant medication with gemfibrozil. The combined use of lovastatin with gemfibrozil should be avoided, unless the benefits are likely to outweigh the increased risks of this drug combination. Other lipid-lowering drugs (other fibrates or ≥1 g/day of niacin): The dose of lovastatin should not exceed 20 mg daily in patients receiving concomitant medication with 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 or danazol, with higher doses of lovastatin: The dose of lovastatin should not exceed 20 mg daily in patients receiving concomitant medication with cyclosporine or danazol. The benefits of the use of lovastatin in patients receiving cyclosporine or danazol should be carefully weighed against the risks of these combinations.
Amiodarone or verapamil: The dose of lovastatin should not exceed 40 mg daily in patients receiving concomitant medication with amiodarone or verapamil. The combined use of lovastatin at doses higher than 40 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy. The risk of myopathy/rhabdomyolysis is increased when either amiodarone or verapamil is used concomitantly with higher doses of a closely related member of the HMG-CoA reductase inhibitor class. Prescribing recommendations for interacting agents are summarized in Table VI (see also CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions; DOSAGE AND ADMINISTRATION).
Interacting Agents | Prescribing Recommendations |
Itraconazole Ketoconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Nefazodone | Avoid Lovastatin |
Gemfibrozil Other fibrates Lipid-lowering doses (≥1g/day) of niacin Danozol | Do not exceed 20 mg lavastatin daily |
Amiodarone Verapamil | Do not exceed 40 mg Lovastatin daily |
Grapefruit juice | Avoid large quantities of grapefruit juice (less than 1 quart daily) |
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 function tests be performed prior to initiation of therapy in patients with a history of liver disease, or when otherwise clinically indicated. It is recommended that liver function tests be performed in all patients prior to use of 40 mg or more daily and thereafter when clinically indicated. Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality(ies) returns to normal. Should an increase in AST or ALT of three times the upper limit of normal or greater persist, withdrawal of therapy with lovastatin is recommended. The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver disease or unexplained transaminase elevations are contraindications to the use of lovastatin. As with other lipid-lowering agents, moderate (less than three times the upper limit of normal) elevations of serum transaminases have been reported following therapy with 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.
| Placebo (N=1663) % | Lovastatin 20 mg q.p.m. (N=1645) % | Lovastatin 40 mg q.p.m. (N=1645) % | Lovastatin 20 mg b.i.d. (N=1646) % | Lovastain 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 |
Dyspepia | 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 vison | 0.8 | 1.1 | 0.9 | 0.9 | 1.2 |
After oral administration of lovastatin to mice, the median lethal dose observed was >15 g/m². Five healthy human volunteers have received up to 200 mg of lovastatin as a single dose without clinically significant adverse experiences. A few cases of accidental overdosage have been reported; no patients had any specific symptoms, and all patients recovered without sequelae. The maximum dose taken was 5-6 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.
The patient should be placed on a standard cholesterol-lowering diet before receiving lovastatin tablets and should continue on this diet during treatment with lovastatin tablets (see NCEP Treatment Guidelines for details on dietary therapy). Lovastatin tablets 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 10-80 mg/day in single or two divided doses; the maximum recommended dose is 80 mg/day. Doses should be individualized according to the recommended goal of therapy (see NCEP Guidelines and CLINICAL PHARMACOLOGY). Patients requiring reductions in LDL-C of 20% or more to achieve their goal (see INDICATIONS AND USAGE) should be started on 20 mg/day of lovastatin tablets. A starting dose of 10 mg may be considered for patients requiring smaller reductions. Adjustments should be made at intervals of 4 weeks or more. Cholesterol levels should be monitored periodically and consideration should be given to reducing the dosage of lovastatin tablets if cholesterol
levels fall significantly below the targeted range.
Dosage in Patients taking Cyclosporine or Danazol
In patients taking cyclosporine or danazol concomitantly with lovastatin (see WARNINGS, Myopathy/Rhabdomyolysis), therapy should begin with 10 mg of lovastatin tablets and should not exceed 20 mg/day.
Dosage in Patients taking Amiodarone or Verapamil
In patients taking amiodarone or verapamil concomitantly with lovastatin tablets, the dose should not exceed 40 mg/day (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions, Other drug interactions).
Adolescent Patients (10-17 years of age) with Heterozygous Familial Hypercholesterolemia
The recommended dosing range is 10-40 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 tablets. 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 tablets are effective alone or when used concomitantly with bile-acid sequestrants. If lovastatin tablets are used in combination with gemfibrozil, other fibrates or lipid-lowering doses (≥1g/day) of niacin, the dose of lovastatin tablets should not exceed 20 mg/day (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions).
Dosage in Patients with Renal Insufficiency
In patients with severe renal insufficiency (creatinine clearance less than 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).
LB0145 - Lovastatin Tablets, USP 10MG Label
Lovastatin 10 mg Front Label
LB0146 - Lovastatin Tablets, USP 20MG Label
Lovastatin 20 mg Front Label
LB0147 - Lovastatin Tablets, USP 40MG Label
Lovastatin 40 mg Front Label
LOVASTATIN
lovastatin tablet |
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Marketing Information | |||
Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
ANDA | ANDA078296 | 03/22/2010 |
LOVASTATIN
lovastatin tablet |
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Marketing Information | |||
Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
ANDA | ANDA078296 | 04/03/2010 |
LOVASTATIN
lovastatin tablet |
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Marketing Information | |||
Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
ANDA | ANDA078296 | 04/10/2010 |
Labeler - International Labs, Inc. (023569924) |
Registrant - International Labs, Inc. (023569924) |
Establishment | |||
Name | Address | ID/FEI | Operations |
Lupin Limited | 677600414 | MANUFACTURE, MANUFACTURE, MANUFACTURE |
Revised: 12/2011 International Labs, Inc.