LOVASTATIN - lovastatin tablet

Stati Uniti - Ingliż - NLM (National Library of Medicine)

Ixtrih issa

Ingredjent attiv:
Lovastatin (UNII: 9LHU78OQFD) (Lovastatin - UNII:9LHU78OQFD)
Disponibbli minn:
Dispensing Solutions, Inc.
INN (Isem Internazzjonali):
Lovastatin
Kompożizzjoni:
Lovastatin 10 mg
Rotta amministrattiva:
ORAL
Tip ta 'preskrizzjoni:
PRESCRIPTION DRUG
Indikazzjonijiet terapewtiċi:
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. Therapy wit
Sommarju tal-prodott:
Lovastatin Tablets USP (white to off white round, unscored tablets) containing 10mg of lovastatin and engraved with “CTI” 141 ----Bottle of 60 (NDC 61442-141-60), Bottle of 100 (NDC 61442-141-01), Bottle of 500 (NDC 61442-141-05), Bottle of 1,000 (NDC 61442-141-10) Lovastatin Tablets USP (white to off white round, unscored tablets) containing 20mg of lovastatin and engraved with “CTI” 142 ---- Bottle of 60 (NDC 61442-142-60), Bottle of 100 (NDC 61442-142-01), Bottle of 500 (NDC 61442-142-05), Bottle of 1,000 (NDC 61442-142-10) Lovastatin Tablets USP (white to off white round, unscored tablets) containing 40mg of lovastatin and engraved with “CTI” 143 ---- Bottle of 60 (NDC 61442-143-60), Bottle of 100 (NDC 61442-143-01), Bottle of 500 (NDC 61442-143-05), Bottle of 1,000 (NDC 61442-143-10)
L-istatus ta 'awtorizzazzjoni:
Abbreviated New Drug Application
Numru ta 'awtorizzazzjoni:
66336-602-30

LOVASTATIN - lovastatin tablet

Dispensing Solutions, Inc.

----------

Lovastatin Tablet USP

Rx only

DESCRIPTION

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

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,

each tablet contains the following inactive ingredients: lactose monohydrate, magnesium stearate,

microcrystalline cellulose, poloxamer, pregelatinized starch, sodium starch glycolate, butylated

hydroxyaniso and talc. Butylated hydroxyanisole (BHA) is added as a preservative.

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 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

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 10-30 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.

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

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

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 I through III for dose response results).

The results of a study in patients with primary hypercholesterolemia are presented in Table I.

TABLE I 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

TRIG.

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 II.

TABLE II 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)

TRIG.

(median)

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 240-300

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 III) in lovastatin treated

patients were dose-related and significantly different from placebo (p≤0.001). These results were

sustained throughout the study.

TABLE III Lovastatin vs. Placebo (Percent Change from Baseline-- Average Values Between

Weeks 12 and 48)

**Patients enrolled

DOSAGE

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

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

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 <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 ≤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 20-40 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.

Atheros cleros is

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 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

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).

TABLE IV 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

TOTAL-C

LDL-C

HDL-C

TG. *

Apolipoprotein B

Placebo

-1.1

-1.4

-2.2

-1.4

-4.4

Lovastatin

-19.3

-24.2

+1.1

-1.9

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: 151.5-283.1 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

TABLE V 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

TOTAL-C

LDL-C

HDL-C

TG. *

Apolipoprotein B

Placebo

+3.6

+2.5

+4.8

-3.0

+6.4

Lovastatin

-22.4

-29.2

+2.4

-22.7

-24.4

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.

INDICATIONS AND USAGE

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.

Hypercholes terolemia

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

), 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, 10-17 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:

***Classification of Hyperlipoproteinemias

IDL = intermediate-density lipoprotein.

Lipid Elevations

Type

Lipoproteins

elevated

major

minor

chylomicrons

↑→C

LDL, VLDL

(rare)

C/TG

VLDL

↑→C

(rare)

chylomicrons, VLDL

↑→C

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:

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

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

(100-129: 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)

††

†††

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.

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

Hypersensitivity to any component of this medication.

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

Pregnancy and lactation. Atherosclerosis is a chronic process and the discontinuation of lipid-

lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of

primary hypercholesterolemia. Moreover, cholesterol and other products of the cholesterol

biosynthesis pathway are essential components for fetal development, including synthesis of steroids

and cell membranes. Because of the ability of inhibitors of HMG-CoA reductase such as lovastatin to

decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis

pathway, lovastatin is contraindicated during pregnancy and in nursing mothers. Lovastatin should be

administered to women of childbearing age only when such patients are highly unlikely to

conceive. If the patient becomes pregnant while taking this drug, lovastatin should be discontinued

immediately and the patient should be apprised of the potential hazard to the fetus (see PRECAUTIONS,

Pregnancy).

WARNINGS

††

†††

Myopathy/Rhabdomyolys is

Lovastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as

muscle pain, tenderness or weakness with creatine kinase (CK) above 10 × 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, musclesymptoms and CK increases resolved

when treatment was promptly discontinued. Periodic CK mdeterminations 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 longstanding

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).

Table VI Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis

Interacting Agents

Prescribing Recommendations

Itraconazole

Ketoconazole

Erythromycin

Clarithromycin

Telithromycin

HIV protease inhibitors Nefazodone

Avoid lovastatin

Gemfibrozil

Other fibrates

Lipid-lowering doses (≥1 g/day) of niacin

Cyclosporine

Danazol

Do not exceed 20 mg lovastatin daily

Amiodarone Verapamil

Do not exceed 40 mg lovastatin daily

Grapefruit juice

Avoid large quantities of grapefruit juice (≥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 recommend that liver function tests

be performed in all patients prior to use of 40mg 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) return 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.

PRECAUTIONS

General

Lovastatin may elevate creatine phosphokinase and transaminase levels (see WARNINGS and

ADVERSE REACTIONS ). This should be considered in the differential diagnosis of chest pain in a

patient on therapy with lovastatin.

Homozygous Familial Hypercholesterolemia

Lovastatin is less effective in patients with the rare homozygous familial hypercholesterolemia,

possibly because these patients have no functional LDL receptors. Lovastatin appears to be more likely

to raise serum transaminases (see ADVERSE REACTIONS) in these homozygous patients.

Information for Patients

Patients should be advised about substances they should not take concomitantly with lovastatin

and be advised to report promptly unexplained muscle pain, tenderness, or weakness (see list

below and WARNINGS ,Myopathy/Rhabdomyolysis ). Patients should also be advised to inform

other physicians prescribing a new medication that they are taking lovastatin.

Drug Interactions

CYP3A4 Interactions

Lovastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not

expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Potent inhibitors

of CYP3A4 (below) increase the risk of myopathy by reducing the elimination of lovastatin. See

WARNINGS, Myopathy/Rhabdomyolysis, and CLINICAL PHARMACOLOGY , Pharmacokinetics.

Itraconazole

Ketoconazole

Erythromycin

Clarithromycin

Telithromycin

HIV protease inhibitors

Nefazodone

Cyclos porine

Interactions with lipid-lowering drugs that can cause myopathy when given alone

The risk of myopathy is also increased by the following lipid-lowering drugs that are not potent

CYP3A4 inhibitors, but which can cause myopathy when given alone.

See WARNINGS, Myopathy/Rhabdomyolysis.

Other drug interactions

Cyclosporine or Danazol: The risk of myopathy/rhabdomyolysis is increased by concomitant

administration of cyclosporine or danazol particularly with higher doses of lovastatin (see WARNING,

Myopathy/Rhabdomyolysis).

Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased when either amiodarone

or verapamil is used concomitantly with a closely related member of the HMG-CoA reductase inhibitor

class (see WARNINGS, Myopathy/Rhabdomyolysis; CLINICAL PHARMACOLOGY,

Pharmacokinetics).

Coumarin Anticoagulants: In a small clinical trial in which lovastatin was administered to warfarin

treated patients; no effect on prothrombin time was detected. However, another HMG-CoA reductase

inhibitor has been found to produce a less than two seconds increase in prothrombin time in healthy

volunteers receiving low doses of warfarin. Also, bleeding and/or increased prothrombin time have

been reported in a few patients taking coumarin anticoagulants concomitantly with lovastatin. It is

recommended that in patients taking anticoagulants, prothrombin time be determined before starting

lovastatin and frequently enough during early therapy to insure that no significant alteration of

prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can

be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose

of lovastatin is changed, the same procedure should be repeated. Lovastatin therapy has not been

associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.

Propranolol: In normal volunteers, there was no clinically significant pharmacokinetic or

pharmacodynamic interaction with concomitant administration of single doses of lovastatin and

propranolol.

Digoxin: In patients with hypercholesterolemia, concomitant administration of lovastatin and digoxin

resulted in no effect on digoxin plasma concentrations.

Oral Hypoglycemic Agents: In pharmacokinetic studies of lovastatin in hypercholesterolemic non-insulin

dependent diabetic patients, there was no drug interaction with glipizide or with chlorpropamide (see

CLINICAL PHARMACOLOGY , Clinical Studies ).

Endocrine Function

HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically

blunt adrenal and/or gonadal steroid production. Results of clinical trials with drugs in this class have

been inconsistent with regard to drug effects on basal and reserve steroid levels. However, clinical

studies have shown that lovastatin does not reduce basal plasma cortisol concentration or impair adrenal

reserve, and does not reduce basal plasma testosterone concentration. Another HMG-CoA reductase

inhibitor has been shown to reduce the plasma testosterone response to HCG. In the same study, the

mean testosterone response to HCG was slightly but not significantly reduced after treatment with

lovastatin 40 mg daily for 16 weeks in 21 men. The effects of HMG-CoA reductase inhibitors on male

fertility have not been studied in adequate numbers of male patients. The effects, if any, on the pituitary-

Large quantities of grapefruit juice (>1 quart daily)

Gemfibrozil

Other fibrates

Niacin (nicotinic acid) (≥1 g/day)

gonadal axis in premenopausal women are unknown. Patients treated with lovastatin who develop

clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be

exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is

administered to patients also receiving other drugs (e.g., ketoconazole, spironolactone, cimetidine) that

may decrease the levels or activity of endogenous steroid hormones.

CNS Toxicity

Lovastatin produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in

clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean

plasma drug levels about 30 times higher than the mean drug level in humans taking the highest

recommended dose (as measured by total enzyme inhibitory activity). Vestibulocochlear Wallerian-like

degeneration and retinal ganglion cell chromatolysis were also seen in dogs treated for 14 weeks at 180

mg/kg/day, a dose which resulted in a mean plasma drug level (C

) similar to that seen with the 60

mg/kg/day dose.

CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell

infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels, were

seen in dogs treated with lovastatin at a dose of 180 mg/kg/day, a dose which produced plasma drug

levels (C

) which were about 30 times higher than the mean values in humans taking 80 mg/day.

Similar optic nerve and CNS vascular lesions have been observed with other drugs of this class.

Cataracts were seen in dogs treated for 11 and 28 weeks at 180 mg/kg/day and 1 year at 60 mg/kg/day.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 21-month carcinogenic study in mice, there was a statistically significant increase in the incidence

of hepatocellular carcinomas and adenomas in both males and females at 500 mg/kg/day. This dose

produced a total plasma drug exposure 3 to 4 times that of humans given the highest recommended dose

of lovastatin (drug exposure was measured as total HMG-CoA reductase inhibitory activity in extracted

plasma). Tumor increases were not seen at 20 and 100 mg/kg/day, doses that produced drug exposures

of 0.3 to 2 times that of humans at the 80 mg/day dose. A statistically significant increase in pulmonary

adenomas was seen in female mice at approximately 4 times the human drug exposure. (Although mice

were given 300 times the human dose [HD] on a mg/kg body weight basis, plasma levels of total

inhibitory activity were only 4 times higher in mice than in humans given 80 mg of lovastatin.)

There was an increase in incidence of papilloma in the non-glandular mucosa of the stomach of mice

beginning at exposures of 1 to 2 times that of humans. The glandular mucosa was not affected. The

human stomach contains only glandular mucosa.

In a 24-month carcinogenicity study in rats, there was a positive dose response relationship for

hepatocellular carcinogenicity in males at drug exposures between 2-7 times that of human exposure at

80 mg/day (doses in rats were 5, 30 and 180 mg/kg/day).

An increased incidence of thyroid neoplasms in rats appears to be a response that has been seen with

other HMG-CoA reductase inhibitors.

A chemically similar drug in this class was administered to mice for 72 weeks at 25, 100, and 400

mg/kg body weight, which resulted in mean serum drug levels approximately 3, 15, and 33 times higher

than the mean human serum drug concentration (as total inhibitory activity) after a 40 mg oral dose. Liver

carcinomas were significantly increased in high-dose females and mid- and high-dose males, with a

maximum incidence of 90 percent in males. The incidence of adenomas of the liver was significantly

increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of

lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of

the eye of rodents) were significantly higher in high dose mice than in controls.

No evidence of mutagenicity was observed in a microbial mutagen test using mutant strains of

Salmonella typhimurium with or without rat or mouse liver metabolic activation. In addition, no evidence

of damage to genetic material was noted in an in vitro alkaline elution assay using rat or mouse

hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in

CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow.

Drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell

formation were seen in dogs starting at 20 mg/kg/day. Similar findings were seen with another drug in

this class. No drug-related effects on fertility were found in studies with lovastatin in rats. However, in

studies with a similar drug in this class, there was decreased fertility in male rats treated for 34 weeks

at 25 mg/kg body weight, although this effect was not observed in a subsequent fertility study when this

same dose was administered for 11 weeks (the entire cycle of spermatogenesis, including epididymal

maturation). In rats treated with this same reductase inhibitor at 180 mg/kg/day, seminiferous tubule

degeneration (necrosis and loss of spermatogenic epithelium) was observed. No microscopic changes

were observed in the testes from rats of either study. The clinical significance of these findings is

unclear.

Pregnancy

Pregnancy Category X

See CONTRAINDICATIONS.

Safety in pregnant women has not been established.

Lovastatin has been shown to produce skeletal malformations in offspring of pregnant mice and rats

dosed during gestation at 80 mg/kg/day (affected mouse fetuses/total: 8/307 compared to 4/289 in the

control group; affected rat fetuses/total: 6/324 compared to 2/308 in the control group). Female rats

dosed before mating through gestation at 80 mg/kg/day also had fetuses with skeletal malformations

(affected fetuses/total: 1/152 compared to 0/171 in the control group). The 80 mg/kg/day dose in mice is

7 times the human dose based on body surface area and in rats results in 5 times the human exposure

based on AUC. In pregnant rats given doses of 2, 20, or 200 mg/kg/day and treated through lactation, the

following effects were observed: neonatal mortality (4.1%, 3.5%, and 46%, respectively, compared to

0.6% in the control group), decreased pup body weights throughout lactation (up to 5%, 8%, and 38%,

respectively, below control), supernumerary ribs in dead pups (affected fetuses/total: 0/7, 1/17, and

11/79, respectively, compared to 0/5 in the control group), delays in ossification in dead pups (affected

fetuses/total: 0/7, 0/17, and 1/79, respectively, compared to 0/5 in the control group) and delays in pup

development (delays in the appearance of an auditory startle response at 200 mg/kg/day and free-fall

righting reflexes at 20 and 200 mg/kg/day).

Direct dosing of neonatal rats by subcutaneous injection with 10 mg/kg/day of the open hydroxyacid

form of lovastatin resulted in delayed passive avoidance learning in female rats (mean of 8.3 trials to

criterion, compared to 7.3 and 6.4 in untreated and vehicle-treated controls; no effects on retention 1

week later) at exposures 4 times the human systemic exposure at 80 mg/day based on AUC. No effect

was seen in male rats. No evidence of malformations was observed when pregnant rabbits were given 5

mg/kg/day (doses equivalent to a human dose of 80 mg/day based on body surface area) or a maternally

toxic dose of 15 mg/kg/day (3 times the human dose of 80 mg/day based on body surface area).

Rare clinical reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase

inhibitors have been received. However, in an analysis† of greater than 200 prospectively followed

pregnancies exposed during the first trimester to lovastatin or another closely related HMG-CoA

reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general

population. This number of pregnancies was sufficient to exclude a 3-fold or greater increase in

congenital anomalies over the background incidence.

Maternal treatment with lovastatin may reduce the fetal levels of mevalonate, which is a precursor of

cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of

lipidlowering drugs during pregnancy should have little impact on the long-term risk associated with

primary hypercholesterolemia. For these reasons, lovastatin should not be used in women who are

pregnant, or can become pregnant (see CONTRAINDICATIONS). Lovastatin should be administered to

women of childbearing potential only when such patients are highly unlikely to conceive and have been

informed of the potential hazards. Treatment should be immediately discontinued as soon as pregnancy

is recognized.

Nursing Mothers

It is not known whether lovastatin is excreted in human milk. Because a small amount of another drug in

this class is excreted in human breast milk and because of the potential for serious adverse reactions in

nursing infants, women taking lovastatin should not nurse their infants (see CONTRAINDICATIONS).

Pediatric Use

Safety and effectiveness in patients 10-17 years of age with heFH have been evaluated in controlled

clinical trials of 48 weeks duration in adolescent boys and controlled clinical trials of 24 weeks

duration in girls who were at least 1 year post-menarche. Patients treated with lovastatin had an adverse

experience profile generally similar to that of patients treated with placebo. Doses greater than 40 mg

have not been studied in this population. In these limited controlled studies, there was no detectable

effect on growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls. See

CLINICAL PHARMACOLOGY,Clinical Studies in Adolescent Patients ; ADVERSE REACTIONS,

Adolescent Patients ; and DOSAGE AND ADMINISTRATION, Adolescent Patients (10-17 years of age)

with Heterozygous Familial Hypercholesterolemia. Adolescent females should be counseled on

appropriate contraceptive methods while on lovastatin therapy (see CONTRAINDICATIONS and

PRECAUTIONS, Pregnancy ). Lovastatin has not been studied in pre-pubertal patients or patients

younger than 10 years of age.

Geriatric Use

A pharmacokinetic study with lovastatin showed the mean plasma level of HMG-CoA reductase

inhibitory activity to be approximately 45% higher in elderly patients between 70-78 years of age

compared with patients between 18-30 years of age; however, clinical study experience in the elderly

indicates that dosage adjustment based on this age-related pharmacokinetic difference is not needed. In

the two large clinical studies conducted with lovastatin (EXCEL and AFCAPS/TexCAPS), 21%

(3,094/14,850) of patients were ≥65 years of age. Lipid-lowering efficacy with lovastatin was at least

as great in elderly patients compared with younger patients, and there were no overall differences in

safety over the 20 to 80 mg/day dosage range (see CLINICAL PHARMACOLOGY ).

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.

ADVERSE REACTIONS

Lovastatin is generally well tolerated; adverse reactions usually have been mild and transient.

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

Gastrointestinal

Abdominal pain

Constipation

Diarrhea

Dyspepsia

Flatulence

Nausea

Musculoskeletal

Muscle cramps

Myalgia

Nervous System/Psychiatric

Dizziness

Headache

Skin

Rash

Special Senses

Blurred vision

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 20-40 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 at doses exceeding

20 mg/day with cyclosporine, gemfibrozil, other fibrates or lipid-lowering doses (≥1 g/day) of niacin

should be avoided (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.

Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-

ocular movement, facial paresis), tremor, dizziness, vertigo, memory loss, paresthesia, peripheral

neuropathy, peripheral nerve palsy, psychic disturbances, anxiety, insomnia, depression.

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.

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 10-17 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

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

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.

DOSAGE AND ADMINISTRATION

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 10-80 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 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 and should not exceed 20

mg/day.

Dosage in Patients taking Amiodarone or Verapamil

In patients taking amiodarone or verapamil concomitantly with lovastatin, the dose should not exceed 40

mg/day (see WARNINGS , Myopathy/Rhabdomyolysis and PRECAUTIONS , Drug Interactions , Other

drug interactions ).

Adolescent Patients (10-17 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. 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.

National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on

Blood Cholesterol Levels in Children and Adolescents. Pediatrics . 89(3):495-501, 1992.

Concomitant Lipid-Lowering Therapy

Lovastatin is effective alone or when used concomitantly with bile-acid sequestrants. If lovastatin is

used in combination with gemfibrozil, other fibrates or lipid-lowering doses (≥1g/day) of niacin, the

dose of lovastatin 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 <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

Lovastatin Tablets USP (white to off white round, unscored tablets) containing 10mg of lovastatin and

engraved with “CTI”

141 ----Bottle of 60 (NDC 61442-141-60), Bottle of 100 (NDC 61442-141-01), Bottle of 500 (NDC

61442-141-05), Bottle of 1,000 (NDC 61442-141-10)

Lovastatin Tablets USP (white to off white round, unscored tablets) containing 20mg of lovastatin and

engraved with “CTI”

142 ---- Bottle of 60 (NDC 61442-142-60), Bottle of 100 (NDC 61442-142-01), Bottle of 500 (NDC

61442-142-05), Bottle of 1,000 (NDC 61442-142-10)

Lovastatin Tablets USP (white to off white round, unscored tablets) containing 40mg of lovastatin and

engraved with “CTI”

143 ---- Bottle of 60 (NDC 61442-143-60), Bottle of 100 (NDC 61442-143-01), Bottle of 500 (NDC

61442-143-05), Bottle of 1,000 (NDC 61442-143-10)

Storage

Store at 20º-25º C (68º-77º F). [See USP Controlled Room Temperature.] Lovastatin Tablets must be

protected from light and stored in a well-closed, light-resistant container.

Manufactured and Distributed By:

Carlsbad Technology, Inc.

Carlsbad, CA 92008

(REV. 11/09)

CTI-13 REV C

Principal Display Panel – Bottle Label

NDC 66336-0602-XX

NDC 66336-0602-30

Lovastatin

Tablets USP

10 mg

Rx Only

LOVASTATIN

lovastatin tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 6 336 -6 0 2(NDC:6 1442-141)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

Lo va sta tin (UNII: 9 LHU78 OQFD) (Lo vastatin - UNII:9 LHU78 OQFD)

Lo va sta tin

10 mg

Inactive Ingredients

Ingredient Name

Stre ng th

la cto se mo no hydra te (UNII: EWQ57Q8 I5X)

ma g nesium stea ra te (UNII: 70 0 9 7M6 I30 )

cellulo se, micro crysta lline (UNII: OP1R32D6 1U)

po lo xa mer 18 8 (UNII: LQA7B6 G8 JG)

So dium Sta rch Glyco la te Type A Po ta to (UNII: 58 56 J3G2A2)

Sta rch, Co rn (UNII: O8 232NY3SJ)

ta lc (UNII: 7SEV7J4R1U)

butyla ted hydro xya niso le (UNII: REK49 6 0 K2U)

Product Characteristics

Color

white (WHITE)

S core

no sco re

S hap e

ROUND (ROUND)

S iz e

6 mm

Flavor

Imprint Code

79 1

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 6 336 -6 0 2-30

30 in 1 BOTTLE

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 759 9 1

11/25/20 0 2

Labeler -

Dispensing Solutions, Inc. (066070785)

Dispensing Solutions, Inc.

Registrant -

PSS World Medical, Inc. (101822682)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Dispensing So lutio ns, Inc.

0 6 6 0 70 78 5

relabel, repack

Revised: 2/2012

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