LOVASTATIN tablet

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Active ingredient:
LOVASTATIN (UNII: 9LHU78OQFD) (LOVASTATIN - UNII:9LHU78OQFD)
Available from:
Golden State Medical Supply
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
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. 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 in Adults .) 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. The
Product summary:
Lovastatin Tablets USP, 10 mg are available as light peach, unscored, round, flat beveled tablets debossed “926” on one side and “TEVA” on the other side. Packaged in bottles of 60 (NDC51407-251-60), 90 (NDC 51407-251-90) and 1000 (NDC 51407-251-10). Lovastatin Tablets USP, 20 mg are available as light blue, unscored, round, flat beveled tablets, debossed “576” on one side and “TEVA” on the other side. Packaged in bottles of 60 (NDC 51407-252-60), 90 (NDC 51407-252-90) and 1000 (NDC 51407-252-10). Lovastatin Tablets USP, 40 mg are available as light green, unscored, round, flat beveled tablets, debossed “928” on one side and “TEVA” on the other side. Packaged in bottles of 60 (NDC 51407-253-60), 90 (NDC 51407-253-90) and 1000 (NDC 51407-253-10). Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Lovastatin Tablets, USP must be protected from light. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. Manufactured In Croatia By: Pliva Hrvatska d.o.o. Zagreb, Croatia Manufactured For: Teva Pharmaceuticals USA, Inc. Parsippany, NJ 07054 Rev. U 7/2020 Marketed/Packaged by: GSMS, Inc. Camarillo, CA USA 93012
Authorization status:
Abbreviated New Drug Application
Authorization number:
51407-251-10, 51407-251-60, 51407-251-90, 51407-252-10, 51407-252-60, 51407-252-90, 51407-253-10, 51407-253-60, 51407-253-90

LOVASTATIN- lovastatin tablet

Golden State Medical Supply

----------

Lovastatin Tablets, USP

Rx only

DESCRIPTION

Lovastatin, USP is a cholesterol lowering agent isolated from a strain of Aspergillus terreus. After oral

ingestion, lovastatin, USP, 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, USP 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. Its structural

formula is:

M.W. 404.55

Lovastatin, USP is a white, nonhygroscopic crystalline powder that is insoluble in water and sparingly

soluble in ethanol, methanol, and acetonitrile.

Lovastatin Tablets, USP are supplied as 10 mg, 20 mg and 40 mg tablets for oral administration. In

addition to the active ingredient lovastatin, USP, each tablet contains the following inactive ingredients:

lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized corn starch.

Butylated hydroxyanisole (BHA) is added as a preservative. Lovastatin Tablets USP, 10 mg also contain

FD&C Yellow #6 Aluminum Lake. Lovastatin Tablets USP, 20 mg also contain FD&C Blue #1

Aluminum Lake. Lovastatin Tablets USP, 40 mg also contain D&C Yellow #10 Aluminum Lake, FD&C

Blue #1 Aluminum Lake, and FD&C Yellow #6 Aluminum Lake.

CLINICAL PHARMACOLOGY

The involvement of low-density lipoprotein cholesterol (LDL-C) in atherogenesis has been well-

documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological

and clinical studies have established that high LDL-C and low high-density lipoprotein cholesterol

(HDL-C) are both associated with coronary heart disease. However, the risk of developing coronary

heart disease is continuous and graded over the range of cholesterol levels and many coronary events

do occur in patients with total cholesterol (total-C) and LDL-C in the lower end of this range.

Lovastatin has been shown to reduce elevated LDL-C concentrations. LDL is formed from very low-

density lipoprotein (VLDL) and is catabolized predominantly by the high affinity LDL receptor. The

mechanism of the LDL-lowering effect of lovastatin may involve both reduction of VLDL-C

concentration, and induction of the LDL receptor, leading to reduced production and /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

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

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

, 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.

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

TABLE I: The Effect of Other Drugs on Lovastatin Exposure When Both Were Coadministered

Number of

Subjects

Dosing of

Coadministered Drug

or Grapefruit Juice

Dosing of

Lovas tatin

AUC Ratio

(with/without

coadministered drug) No

Effect = 1.00

Lovas tatin

Lovastatin acid

Gemfibrozil

600 mg BID for 3 days

40 mg

0.96

2.80

Itraconazole

200 mg QD for 4 days

40 mg on Day

> 36

100 mg QD for 4 days

40 mg on Day

> 14.8

15.4

Grapefruit Juice

(high dose)

200 mL of double-

strength TID

80 mg single

dose

15.3

Grapefruit Juice

(low dose)

8 oz (about 250 mL) of

single-strength

for 4

days

40 mg single

dose

1.94

1.57

Cyclosporine

Not described

10 mg QD for

10 days

5 to 8 fold

Number of

Subjects

Dosing of

Coadministered Drug

or Grapefruit Juice

Dosing of

Lovas tatin

AUC Ratio

(with/without

coadministered drug) No

Effect = 1.00

Total Lovastatin acid

Diltiazem

120 mg BID for 14 days

20 mg

3.57

1

2

3

4

4

5

6

5

7

8

9

1

10

10

1. Results based on a chemical assay.

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

3. 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.

4. Estimated minimum change.

5. The effect of amounts of grapefruit juice between those used in these two studies on lovastatin

pharmacokinetics has not been studied.

6. 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.

7. 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.

8. Cyclosporine-treated patients with psoriasis or post kidney or heart transplant patients with stable

graft function, transplanted at least 9 months prior to study.

9. ND = Analyte not determined.

10. 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

TOTAL-C

LDL-C

HDL-C

LDL-C/HDL-C TOTAL-C/HDL-C TG.

Placebo

Lovastatin

10 mg q.p.m.

20 mg q.p.m.

10 mg b.i.d.

40 mg q.p.m.

20 mg b.i.d.

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

TOTAL-C

(mean)

LDL-C

(mean)

HDL-C

(mean)

LDL-

C/HDL-C

(mean)

TOTAL-

C/HDL-C

(mean)

VLDL-C

(median)

(mean)

Lovastatin

20 mg b.i.d.

40 mg b.i.d.

Cholestyramine

12 g b.i.d.

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)

DOSAGE

TOTAL-C

(mean)

LDL-C

(mean)

HDL-C

(mean)

LDL-C/HDL-

C (mean)

TOTAL-

C/HDL-C

(mean)

(median)

Placebo

1663

+0.7

+0.4

+2.0

+0.2

+0.6

Lovastatin

20 mg q.p.m.

1642

+6.6

40 mg q.p.m.

1645

+7.2

20 mg b.i.d.

1646

+8.6

40 mg b.i.d.

1649

+9.5

1. 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 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

1

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 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).

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

TOTAL-C

LDL-C

HDL-C

Apolipoprotein B

Placebo

-1.1

-1.4

-2.2

-1.4

-4.4

Lovastatin

-19.3

-24.2

+1.1

-1.9

1

1. data presented as median percent changes

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).

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)

DOSAGE

TOTAL-C

LDL-C

HDL-C

Apolipoprotein B

Placebo

+3.6

+2.5

+4.8

-3.0

+6.4

Lovastatin

-22.4

-29.2

+2.4

-22.7

-24.4

1. data presented as median percent changes

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.

INDICATIONS AND USAGE

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 in Adults.)

1

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.

Hypercholes terolemia

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.

Classification of Hyperlipoproteinemias

Lipid Elevations

Type

Lipoproteins elevated

major

minor

chylomicrons

↑→C

LDL, VLDL

III (rare)

C/TG

VLDL

↑→C

V (rare)

chylomicrons, VLDL

↑→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 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 x (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 are not indicated.

The National Cholesterol Education Program (NCEP) Treatment Guidelines are summarized below:

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)

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%: ≥

10 year risk < 10%: ≥ 160

0 to 1 Risk factor

< 160

≥ 160

≥ 190 (160 to 189: LDL-

lowering drug optional)

1. CHD, coronary heart disease

2. 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.

3. 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.

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 Treatment 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

< 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.

CONTRAINDICATIONS

Hypersensitivity to any component of this medication.

Active liver disease or unexplained persistent elevations of serum transaminases (see WARNINGS).

Concomitant administration with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole,

posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin,

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